Descriptive reference is made to catechol-containing protein tyrosine kinase receptor antagonists which are useful in treating hyperproliferative diseases in U.S. application Ser. No. 08/653,786 filed May 28, 1996, now U.S. Pat. No. 5,747,498 issued May 5, 1998; International application Ser. No. PCT/IB95/00436 filed Jun. 6, 1995, designating the United States, and published as WO 96/30347 on Oct. 3, 1996; and U.S. application Ser. No. 60/020,491 filed Jun. 24, 1996, now abandoned, filed as International application Ser. No.
PCT/IB97/675 filed Jun. 11, 1997, designating the United States, and published as WO 97/49688 on Dec. 31, 1997; the disclosures of all of which are incorporated herein by reference in their entireties.
Descriptive reference is also made to non-catechol-containing protein tyrosine kinase receptor antagonists useful in treating hyperproliferative diseases in U.S. application Ser. No. 08/682,565 filed Jan, 27, 1995, now U.S. Pat. No. 5,736,534 issued Apr. 7, 1998, corresponding to International application Serial No. PCT/IB95/00061 filed Jan. 27, 1995, and published as WO 95/23141 on Aug. 31, 1995; U.S. application Ser. No. 08/449,381 filed May 23, 1995, now U.S. Pat. No. 5,593,997 issued Jan. 14, 1997; and International application Seri. No. PCT/US95/07881 filed Jun. 7, 1995, designating the United States, and published as WO 96/40142 on Dec. 19, 1996; the disclosures of all of which are incorporated herein by reference in their entireties.
The present invention is in the field of compositions of matter, and pharmaceutical compositions and methods of treatment utilizing one or more of said compositions of matter as the active ingredient and the active agent with respect thereto, wherein said composition of matter comprises an indazole moiety as an essential feature of its overall chemical structure. Further, said indazole constitutes a bioisosteric replacement of a catechol moiety or functional derivative thereof in an original composition of matter in which said catechol moiety has been subject to bioisosteric replacement by said indazole moiety. The type and extent of biological activity found in said original composition of matter is retained and even increased and improved in said indazole bioisostere thereof.
The term xe2x80x9ccatecholxe2x80x9d as used herein refers to 1,2-benzenediol, sometimes referred to as xe2x80x9cpyrocatecholxe2x80x9d, which may be represented by Formula (1.0): 
The name is derived from catechin or catechu which in turn refer to a slightly more complex composition derived from Acacia catechu. As a distinct chemical group or moiety, catechol is a key component of number of different molecules having pharmacological activity and consequently, usefulness as therapeutic agents.
The present invention is concerned with the discovery that the indazole nucleus is a moiety which is capable of being a bioisostere replacement for a catechol moiety comprising a functionally essential part of the makeup of compounds which are therapeutically active as a result of their fundamental operation as endogenous ligands, enzyme inhibitors, receptor antagonists, substrate mimics, regulating and signalling entities such as the chemokines, by means of which they carry out essential metabolic functions in the body.
Thus, in accordance with the present invention it has been discovered that the indazole nucleus is a bioisostere replacement for the catechol moiety which is an essential part of many classes and types of compounds, including numerous drugs which have been and will in the future be created and developed for therapeutic treatments as detailed further herein. This bioisostere replacement will be better understood from the following structural representation of the catechol moiety and the indazole moiety which replaces it, which may be represented respectively by Formulas (1.1) and (1.2): 
It will be understood that the substituent xe2x80x9cR3xe2x80x9d in the above Formulas (1.1) and (1.2) is a generalized illustration, ie., it represents the possibility of more than one substituent as well as substitution at more than one position of the phenyl ring, and further, includes essentially all of the structural elements of all of the catechol-containing compounds for which the indazole-for-catechol bioisostere replacement of the present invention may be carried out.
Consequently, it will be understood that the terms xe2x80x9cbioisosterexe2x80x9d, xe2x80x9cbioisosteric replacementxe2x80x9d, xe2x80x9cbioisosterismxe2x80x9d and closely related terms as used herein have the same meanings as those generally recognized in the art. Bioisosteres are atoms, ions, or molecules in which the peripheral layers of electrons can be considered identical. The term bioisostere is usually used to mean a portion of an overall molecule, as opposed to the entire molecule itself. Bioisosteric replacement involves using one bioisostere to replace another with the expectation of maintaining or slightly modifying the biological activity of the first bioisostere. The bioisosteres in this case are thus atoms or groups of atoms having similar size, shape and electron density.
Included within the scope of the bioisostere indazole-for-catechol replacements of the present invention are a number of catechol-containing compounds which have a third hydroxy or derivative group, xe2x80x94ORX, on a third carbon of the phenyl ring, usually adjacent to one of the two carbons comprising the catechol moiety. Compounds of this type may be illustrated by Formula (1.3) and exemplified by cinepazet of Formula (6.8): 
In this type of catechol moiety, which is described herein as having an xe2x80x9cadditional xe2x80x94ORX substituentxe2x80x9d, the indazole-for-catechol bioisostere replacement of the present invention may xe2x80x9cincludexe2x80x9d or xe2x80x9cexcludexe2x80x9d said additional xe2x80x94ORX substituent.
Where the additional xe2x80x94ORX substituent is included in the bioisostere replacement, all three of the xe2x80x94OR groups, including said additional substituent xe2x80x94ORX, are replaced by the indazole group, in effect as though the additional xe2x80x94ORX substituent were not present at all. On the other hand, where said additional xe2x80x94ORX substituent is excluded from the bioisostere replacement, it will remain as a substituent at the same position of the phenyl ring, but as part of the indazole ring. The case of indazole-for-catechol bioisostere replacement which includes said additional xe2x80x94ORX substituent may be illustrated by Formulas (1.3) and (1.4): 
The case of indazole-for-catechol bioisostere replacement which excludes said additional xe2x80x94ORX substituent may be illustrated by Formulas (1.3) and (1.5): 
Both the inclusionary and exclusionary indazole-for-catechol bioisostere replacements described above may be further illustrated in the case of cinepazet by Formulas (1.6) and (1.7), respectively, as follows: 
Bioisosterism has often been viewed as arising from a reasonable expectation that a proposed bioisosteric replacement will result in maintenance of similar biological properties. Such a reasonable expectation may be based on structural similarity alone. This is especially true in those cases where a number of particulars are known regarding the characteristic domains of the receptor, etc. involved, to which the bioisosteres are bound or which works upon said bioisosteres in some manner. In the case of the present invention, however, there is a complete lack of such structural similarity, and the significant number of different therapeutic classes in which this indazole-for-catechol bioisostere replacement may be successfully employed belies any straightforward predictability. These various therapeutic classes will be reviewed briefly before being described in detail further below.
One class of catechol-containing compounds having significant pharmacological and therapeutic activity that is very well-known are the catecholamines. These catecholamines, typically epinephrine, norepinephrine and dopamine, are released by the sympathetic nervous system and by the adrenal medulla and perform an important function in the mammalian body by regulating innumerable aspects of its physiology, especially the myriad responses of said body to multiple stresses which it encounters every day. The chemical structure of norepinephrine is representative and may be illustrated by Formula (2.0): 
Numerous sympathomimetic drugs, which act as agonists and antagonists for the receptors of said catecholamines utilize the catechol component as a key part of their overall chemical structure. The major classes of agonists and antagonists for said receptors of catecholamines, to which the indazole-for-catechol bioisostere replacement of the present invention is applicable, are described in the paragraphs which follow.
Cholinesterase inhibitors, i.e., anticholinesterase agents which have a catechol moiety as a central and characteristic portion of their overall chemical structure, are active in the inhibition of acetylcholinesterase, with the consequent accumulation of endogenous acetylcholine. As a result, such catechol-containing anticholinesterase agents have therapeutic utility in the treatment of glaucoma, the facilitation of gastrointestinal and bladder motility, and in combatting cognitive dysfunction and other aspects of Alzheimer""s disease.
Acetylcholinesterase is the enzyme responsible for the breakdown of the neurotransmitter acetylcholine and thus in terminating its action at the junctions of various cholinergic nerve endings with their effector organs or postsynaptic sites. Anticholinesterase agents inhibit acetylcholinesterase and thereby cause acetylcholine to accumulate at cholinergic receptor sites. Their actions are thus cholinomimetic and produce effects equivalent to excessive stimulation of cholinergic receptors throughout the central and peripheral nervous systems. Cholinergic neurons are widely distributed in the body, and many anticholinesterase agents have been discovered to date, several of them being widely used as therapeutic agents.
Adrenergic xcex11-antagonists and xcex21-agonists interact with certain of the four different catecholamine receptors in mammals, each of which has a distinctive response pattern.
These receptors have been designated the xcex11-, xcex12-, xcex21-, and xcex22-adrenergic receptors, and they occur in many different tissues and have various physiological effects. In particular, they play a very significant role in maintaining the activities of the sympathetic nervous system, which is responsible for mediating or regulating innumerable bodily functions. The areas controlled by the sympathetic nervous system are so essential and so diverse that it has long been the focus of medicinal chemists endeavoring to discover drugs which can antagonize, modify or even imitate its activity and thus become useful in the treatment of such important clinical conditions as hypertension, arrhythmias, cardiovascular shock, asthma, anaphylactic reactions, and migraine headaches.
For example, xcex11-adrenergic receptors may be found in the intestine where they are responsible for decreased motility, in the salivary glands where they regulate potassium and water secretion, in the iris of the eye where they play a role in contraction of the iris, in vascular smooth muscle where they mediate contraction, and in the tissue of the heart where they play a role in providing increased contractile force and in regulating the rhythm of heart muscle contractions.
The xcex12-adrenergic receptors are located in the stomach where they result in decreased motility, in fat cells where they cause decreased lipolysis, in blood platelets where they are part of the process of aggregation, in pancreatic xcex2 cells where they have the effect of decreasing secretion, and in vascular smooth muscle where they regulate contraction. There are also tissues in which the particular xcex1-adrenergic receptor subtype has not yet been identified. These include the bladder sphincter where they effect contraction, and in arterioles found in the skin and mucosa, where they mediate constriction.
The xcex21-adrenergic receptors occur in heart tissue where they provide increased rate, force and depth of contraction. The xcex22-adrenergic receptors occur in bronchial and lung tissue where they produce muscle relaxation, in liver tissue where they mediate increased glycogenolysis, and in the intestine where they are also responsible for decreased motility.
The mediatory contribution of the xcex11-, xcex12-, xcex21-, and xcex22-adrenergic receptors in the body can be modified or eliminated by the use of therapeutic agents which have antagonistic activity. Such antagonists tend to nullify the action of the active agents, e.g., neurotransmitters such as dopamine, by being bound to said receptors without, however, eliciting a biological response. The inhibitory potency of an antagonist is largely a measure of the ability of said antagonist to be bound preferentially and tightly to said receptor so as to competitively displace the natural ligand for said receptor. Accordingly, a compound which has the essential structural features of a catecholamine or catechol that are required for it to be competitively bound to one or more of the xcex11-, xcex12-, xcex21-, and xcex22-adrenergic receptors, can function as a pharmaceutical active ingredient. Such an active ingredient would be suitable for the therapeutic treatment of any disease or condition whose treatment or prevention, or the amelioration of whose symptoms would tend to be accomplished by the antagonism, i.e., blockade of any one or more of the receptors for which a catecholamine or catechol type compound is the natural ligand in the body.
In the same manner, the mediatory contribution of the xcex11-, xcex12-, xcex21-, and xcex22-adrenergic receptors in the body can be modified or enhanced by the use of therapeutic agents which have agonist activity. Such agonists are structural analogs of catecholamines or catechols which bind productively to a receptor and mimic its biological activity. Thus, an agonist is comparable to an alternative substrate for an enzyme. The binding of the agonist to the receptor is productive in that the metabolic response which is evoked is comparable to that which would result if the natural ligand were bound to said receptor. Accordingly, in the case of agonists a compound which has the essential structural features of a catecholamine or catechol that are required for it not only to be bound to one or more of the xcex11-, xcex12-, xcex21-, and xcex22-adrenergic receptors, but also for it to be capable of producing a positive metabolic response, can function as a pharmaceutical active ingredient. Such an active ingredient would be suitable for the therapeutic treatment of any disease or condition whose treatment or prevention, or the amelioration of whose symptoms would tend to be accomplished by agonist activity, i.e., by being bound to any one or more of the receptors for which a catecholamine or catechol type compound is the natural ligand in the body, and further producing a positive metabolic response, usually of the type produced by said natural ligand.
An example of a xcex21-agonist is the active therapeutic agent isoproterenol, which may be represented by Formula (3.0): 
Calcium channel antagonists comprise numerous endogenous ligands acting on important calcium channel receptors and thereby carrying out essential metabolic, especially cardiovascular functions in the body. Calcium channel antagonists, particularly those of the verapamil type, have a catechol moiety as a central and characteristic portion of their overall chemical structure, and they are therapeutically useful in the area of antihypertensive treatment, and in the cardiovascular field they are especially useful, often having activity as antianginal and antiarrhythmic agents in addtion to their antihypertensive utility. Calcium channel antagonists are especially useful in the treatment of variant agina, exertional angina, unstable angina, hypertension, myocardial ischemia, arrhythmia, and migraine prophylaxis.
Other calcium channel antagonists and related compounds having a catechol moiety as an essential part of their overall chemical structure, for which the indazole bioisosteres of the present invention possess equivalent or improved biological activity, comprise gallopamil; fantofarone, which possesses calcium transport inhibitory properties, as well as bradycardic, hypotensive and antiadrenergic properties, for which the indazole replacement bioisosteres are useful in the treatment of angina pectoris, hypertension, arrhythmia and cerebral circulatory insufficiency, as well as in the antitumor field, where it is a potentiator of anticancer chemotherapeutic agents; trimetazidine, which is a peripheral vasodilator whose action is exerted both on the peripheral circulation and on the coronary arteries, a mechanism involving the smooth muscle fibers of the vessel walls of the circulatory system and not the autonomous nervous system, for which the indazole replacement bioisosteres are useful in treating various circulatory disorders such as arteritis or coronary insufficiency; lomerizine, for which the indazole replacement bioisosteres are useful as agents for improving cerebrovascular diseases of humans, and in particular are antimigraine agents; and zatebradine, for which the indazole replacement bioisosteres have long-lasting bradycardiac activity and reduce the oxygen requirements of the heart, with only slight side effects such as antimuscarinic activity.
Cerebrovascular diseases, which are beneficially treated with the indazole replacement bioisosteres of the present invention, include intracranial hemorrhages such as intracerebral hemorrhage or subarachnoid hemorrhage, as well as cerebral infarctions such as cerebral thrombosis or cerebral embolus, transient ischemic attack, and hypertensive encephalopathy. A key mechanism in these diseases is infaction of brain parenchymal tissue resulting directly from hemorrhage, thrombus, or an embolus within the brain, which leads in turn to glucose and oxygen insufficiency, depriving the neurons of needed sources of energy. Functional and organic disturbances result in the ischemic area. Consequently, the indazole replacement bioisosteres of the present invention act as therapeutic agents which supply or enhance the supply of glucose and oxygen to the ischemic area by increasing cerebral blood flow, and are, therefore, effective for the treatment and prevention of such cerebrovascular diseases.
Antineoplastic and antiproliferative agents of the present invention include indazole bioisostere replacement compounds based on trimetrexate, which is an antifolate, i.e., an inhibitor of dihydrofolate reductase, and related to methotrexate, which has provided consistent cure of choriocarcinoma. The indazole replacement bioisosteres based on trimetrexate are lipid-soluble folate antagonists which facilitate penetration of the blood-brain barrier. These bioisosteres may also be used in the therapy of psoriasis, a non-neoplastic disease of the skin characterized by abnormally rapid proliferation of epidermal cells, as well as for the beneficial treatment of Pneumocystis carinii. 
Therapeutic agents of the present invention useful in the treatment of neoplastic diseases also comprise indazole replacement bioisosteres which are protein tyrosine kinase inhibitors. Protein tyrosine kinase inhibitors play a fundamental role in signal transduction pathways, and deregulated protein tyrosine kinase activity has been observed in many proliferative diseases such restenosis in addition to cancer and psoriasis. A number of tumor types have disfunctional growth factor receptor protein tyrosine kinases which result in inappropriate mitogenic signalling; consequently, the indazole replacement bioisosteres are useful for the therapeutic treatment of cancer based on their inhibition of protein tyrosine kinases including particularly epidermal growth factor-receptor protein tyrosine kinase (EGF-R PTK). Especially potent and selective inhibitors of epidermal growth factor-receptor protein tyrosine kinases are indazole replacement bioisosteres which are 4-anilino-quinazolines, e.g., the compound PD-153,035.
Indazole replacement bioisosteres of the present invention also include those wherein the 4-position is occupied by bicyclic aminoheteroaromatic moieties or by heterocyclyl-substituted-6,7-dimethoxy-quinazolines, e.g., those which are the indazole replacement equivalent of the dihydro-indolyl compound CP-292,597. Also included are those where the anilino nitrogen is methylated or replaced by oxygen or sulfur; a phenoxyanilino moiety is used; or the analogous phenethylamino moiety is present. Further included are those bioisosteres which are selective EGF-R PTK inhibitors and are quinazoline derivatives which have various substituents in the anilino side chains, e.g., an ethynyl moiety as in the bioisostere equivalent of CP-358,774, or as in bioisosteres which are 4-indolyl compounds.
Modifications of the class of indazole replacement bioisostere comprising 4-anilino quinazoline moieties described above have not been limited to the 4-anilino group alone. Basic amino side chains have been used in the 6-position of the quinazoline ring and various substituents have been added to the 4-anilino moiety in order to improve solubility of the 4-anilino-quinazoline bioisosteres, as in the indazole replacement equivalent of ZD-1839.
Phosphodiesterase 4 (PDE4) inhibitors are another class of catechol-containing compounds having significant pharmacological activity Phosphodiesterase-4 is a cAMP-specific phosphodiesterase which plays an important role in the regulation of inflammatory and immune cell activation. A significant variety of different structural types of compounds active as PDE-4 inhibitors has been reported, and PDE isozymes have been characterized in cardiac muscle, and airway and arterial smooth muscles. Attention has also been focused on a high-affinity allosteric binding site which is abundant in brain PDE4 isozyme, whose differential modulation relative to the cAMP catalytic site has yielded drugs with greater therapeutic utility. Rolipram, which contains catechol as a key part of its overall chemical structure, is representative of this type of PDE4 inhibitor and may be depicted in accordance with Formula (4.0): 
Thus, the present invention as it relates to PDE4 inhibitors includes compounds having therapeutic usefulness based on the activity thereof as phosphodiesterase-4 inhibitors comprising an indazole as one essential component of their overall chemical structure, wherein said indazole constitutes a bioisosteric replacement of a catechol component or functional derivative thereof in a known compound having the same said therapeutic usefulness based on its activity as a phosphodiesterase-4 inhibitor and the same remaining said components of its overall chemical structure. In particular, this therapeutic usefulness includes treating asthma.
The present invention also includes a method of treating asthma using a known compound having a catechol moiety or functional derivative thereof as one essential component of its overall chemical structure, the improvement consisting of using a compound having an indazole moiety as one essential component of its overall chemical structure and having the same remaining said components of its overall chemical structure, wherein said indazole moiety constitutes a bioisosteric replacement for said catechol moiety, and wherein said compound is useful for treating asthma.
The present invention as it relates to PDE4 inhibitors also includes compounds useful in treating or preventing one or members selected from the groups of diseases and conditions consisting essentially of (1) inflammatory diseases and conditions comprising: joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis, and Crohn""s disease; (2) respiratory diseases and conditions comprising: asthma, acute respiratory distress syndrome, chronic pulmonary inflammatory disease, bronchitis, chronic obstructive airway disease, and silicosis; (3) infectious diseases and conditions comprising: sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, fever and myalgias due to bacterial, viral or fungal infection, and influenza; (4) immune diseases and conditions comprising: autoimmune diabetes, systemic lupus erythematosis, graft vs. host reaction, allograft rejections, multiple sclerosis, .psoriasis, and allergic rhinitis; and (5) other diseases and conditions comprising: bone resorption diseases; reperfusion injury; cachexia secondary to infection or malignancy; cachexia secondary to human acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV) infectioin, or AIDS related complex (ARC); keloid formation; scar tissue formation; type 1 diabetes mellitus; and leukemia; wherein said compound comprises an inhibitor of phosphodiesterase isozyme 4 (PDE4).
Especially important among the above-recited diseases and conditions which may be treated using the indazole bioisostere replacement compounds of the present invention are the inflammatory diseases and conditions and the respiratory diseases and conditions. Among the inflammatory diseases and conditions which are especially significant with regard to successful treatment using the compounds of the present invention comprise: joint inflammation, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease. Among the respiratory diseases and conditions which are especially significant with regard to successful treatment using the compounds of the present invention comprise: asthma, acute respiratory distress syndrome, and bronchitis.
The expression xe2x80x9ctreating or preventingxe2x80x9d, as used herein with regard to the administration of the compounds of the present invention for therapeutic purposes in the case of various members selected from the many groups of diseases and conditions specifically recited herein, is intended to denote both the therapeutic objective of said administration as well as the therapeutic results actually achieved by said administration. The extent of therapy accomplished by administration of the compounds of the present invention may range from an amelioration to a significant diminishing of the course of the disease involved, and beyond to active treatment of said disease, including a reversal of the disease process itself which is present. The higher or highest degrees of therapeutic effectiveness result in the prevention of any injury, damage, deterioration, or loss of body tissues or organs and basic body functions subsequent to the early stages of degeneration and decline in said body tissues or organs and basic body functions at the onset of the disease involved.
The expression xe2x80x9cthe early stages of degeneration and decline in body tissues or organs and basic body functionsxe2x80x9d is intended to mean the very beginning of the initial pathologic changes in said body tissues or organs and basic body functions which define and are the result of a disease process. Said pathologic changes with respect to tissues and organs include changes in the composition and cohesiveness; form and makeup; rigidity, strength, resilience, elasticity, conformational integrity and stability, density, tensile strength and other measures of physical quality; abundance and extent of its presence throughout the body; viability and regenerative capability on both a micro- and macro-level; and the ability to successfully resist various kinds of external stresses including mechanical force and invasion by microorganisms; of said tissues and organs from that present before the onset of said disease process, which result in a degradation and decline of the beneficial and necessary properties characterizing said tissues and organs.
Pathologic changes with respect to body functions are those which inherently arise from the changes above-described with respect to said tissues and organs, and which also, consequently, result in a degradation and decline in the beneficial and necessary performance which characterizes the normal and proper operation of said body functions. These pathologic changes, both with regard to tissues or organs and with respect to body functions, especially include improper repair of the above-discussed early stages of degeneration and decline.
(I) Bioisostere Replacement Compounds Active As Cholinesterase Inhibitors
The present invention relates to the discovery that the indazole nucleus is a bioisostere replacement for the catechol moiety of numerous endogenous ligands acting on important cholinergic receptors and thereby carrying out essential metabolic functions in the body. The present invention relates in particular to indazole-for-catechol bioisostere replacements active as cholinergic antagonists and anticholinesterase agents, comprising a compound of Formulas (5.10) or (5.11):
(I) 
wherein
RC1 is a member independently selected from the group consisting essentially of hydrogen; hydroxy; xe2x80x94Oxe2x80x94(C1-C4)alkyl; and phenyl substituted by 0 to 2 substituents Rs where Rs is a member independently selected from the group consisting essentially of Br, Cl, or F; (C1-C4)alkoxy; and CF3 
RA1 is a member independently selected from the group consisting essentially of hydrogen; (C1-C9) alkyl; xe2x80x94(CH2)n(C3-C10) cycloalkyl wherein n is 0 to 2; xe2x80x94(C1-C6) alkyl(C1-C6) alkoxy; (C2-C6) alkenyl; xe2x80x94(CH2)n(C3-C9) heterocyclyl wherein n is 0 to 2; and xe2x80x94(Zxe2x80x2)b(Zxe2x80x3)c(C6-C10) aryl wherein b and c are each independently 0 or 1, Zxe2x80x2 is (C1-C6) alkylene or (C2-C6) alkenylene, and Zxe2x80x3 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2, or xe2x80x94N(R9)xe2x80x94, and wherein said alkyl, alkenyl, alkoxyalkyl, heterocyclyl, and aryl moieties of said RA1 groups are substituted by 0 to 3 substituents independently selected from halo; hydroxy; (C1-C5) alkyl; (C2-C5) alkenyl; (C1-C5) alkoxy; (C3-C6) cycloalkoxy; trifluoromethyl; nitro; xe2x80x94C(xe2x95x90O)OR9; xe2x80x94C(xe2x95x90O)NR9R10, xe2x80x94NR9R10, and xe2x80x94S(xe2x95x90O)2NR9R10;
wherein preferred embodiments, said aryl moiety comprises a membere selected from the group consisting essentially of phenyl; naphthyl; indenyl (from 2,3-dihydro-1H-indene); indanyl; and fluorenyl (from 9-H-fluorene);
wherein more preferred embodiments said aryl moiety comprises a member independently selected from the group consisting essentially of phenyl and indanyl;
where in preferred embodiments, said heterocyclyl moiety comprises a member independently selected from the group consisting essentially of acridinyl; benzimidazol; benzodioxolane; 1,3-benzodioxol-5-yl; benzo[b]furanyl; benzo[b]thiophenyl; benzoxazolyl; benzthiazolyl; carbazolyl; cinnolinyl; 2,3-dihydrobenzofuranyl; 1,3-dioxane; 1,3-dioxolane; 1,3-dithiane; 1,3-dithiolane; furanyl; imidazolidinyl; imidazolinyl; imidazolyl; 1H-indazolyl; indolinyl; indolyl; 3H-indolyl; isoindolyl; isoquinolinyl; isothiazolyl; isoxazolyl; morpholinyl; 1,8-naphthyridinyl; oxadiazolyl; 1,3-oxathiolane; oxazolidinyl; oxazolyl; oxiranyl; parathiazinyl; phenazinyl; phenothiazinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; pteridinyl; pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolo[1,5-c]triazinyl; pyrazolyl; pyridazinyl; pyridyl; pyrimidinyl; pyrimidyl; pyrrolyl; pyrrolidinyl; purinyl; quinazolinyl; quinolinyl; 4H-quinolizinyl; quinoxalinyl; tetrazolidinyl; tetrazolyl; thiadiazolyl; thiazolidinyl; thiazolyl; thienyl; thiomorpholinyl; triazinyl; and triazolyl; and
where in more preferred embodiments said heterocyclyl moiety comprises a member independently selected from the group consisting essentially of pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl;
R9 and R10 are independently hydrogen or (C1-C4) alkyl substituted by 0 to 3 fluorine atoms;
RB1 is a member independently selected from the group consisting essentially of hydrogen; (C1-C9) alkyl; (C2-C3) alkenyl; phenyl; (C3-C7) cycloalkyl; and xe2x80x94(C1-C2) alkyl(C3-C7) cycloalkyl; wherein said alkyl, alkenyl and phenyl RB1 groups are substituted with 0 to 3 substituents independently selected from the group consisting essentially of methyl; ethyl; trifluoromethyl; and halo; and
R1a and R1b are each individually and independently a member selected from the group consisting essentially of hydrogen and the substituents defined by partial Formulas (5.12); (5.14); (5.16); (5.18); (5.19); (5.21); (5.23); (5.25); (5.26); and (5.28) below, provided that both of R1a and R1b cannot be hydrogen at the same time;
wherein preferred embodiments comprise compounds where one of R1a and R1b is independently selected as hydrogen; and
wherein said substituents in addition to hydrogen which define each of R1a and R1b comprise a member independently selected from the group consisting essentially of the moieties of partial Formulas (5.12); (5.14); (5.16); (5.18); (5.19); (5.21); (5.23); (5.25); (5.26); and (5.28):
(I-A) 
wherein R2, R3, and R4 are independently selected from the group consisting essentially of hydrogen and (C1-C4) alkyl substituted by 0 to 3 substituents R5, where the substituent R5 is selected from the group consisting essentially of fluorine, chlorine, methyl, trifluoromethyl hydroxy, and methoxy;
(I-B) R1a is R6 and R1b is the group of partial Formula (5.14): 
wherein R6 is a member independently selected from the group consisting essentially of (C1-C4) alkyl; (C1-C4) alkoxy; and hydroxy;
(I-C) 
wherein R8, R9 and R10 are independently selected from the group consisting essentially of hydrogen and (C1-C4) alkyl substituted by 0 to 3 substituents is a member independently selected R5, where the substituent R5 is as defined herein.
(I-D) R1a and R1b are taken together to form the moiety of partial Formula (5.18): 
wherein p is 0 or p is 1 and W is xe2x80x94CH2xe2x80x94 or xe2x80x94NHxe2x80x94; R12 is absent or is (C1-C4)alkyl; R1A and R1B are as defined herein; and R13 is xe2x80x94CH3 or is the remainder of the moiety of Formula (5.18) whereby a bis compound is formed as represented by partial Formula (5.19): 
wherein HX is an acid addtion salt,
(I-E) 
wherein R14, R15, and R16 are each a member independently selected from the group consisting essentially of xe2x80x94NH2; xe2x80x94NH(C1-C4) alkyl; and xe2x80x94N[(C1-C4)]alkyl2, where the alkyl groups are selected independently of each other,
(I-F) 
wherein the moiety 
represents the residue of a saturated secondary heterocyclic base having 4, 5, 6, or 7 atoms in the ring, where X is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94; and preferably said secondary heterocyclic base is a member selected from the group consisting essentially of pyrrolidine, 1,3-thiazolidine, imidazolidine, 1,2-oxazolidine, 1,3-oxazolidine, piperidine, piperazine, tetrahydro-1,2-oxazine, tetrahydro-1,3-oxazine, tetrahydro-1,4-oxazine, i.e., morpholine, tetrahydro-1,4-thiazine, and perhydroazepine;
(I-G) 
wherein R14 is as defined herein; and R18 is (C1-C4) alkyl or (C2-C4) alkenyl where said alkyl and alkenyl groups are substituted by 0 to 3 substituents R5, where the substituent R5 is selected from the group consisting essentially of fluorine, chlorine, methyl, trifluoromethyl hydroxy, and methoxy;
(I-H) R1a and R1b are taken together to form the moiety: 
wherein the dashed line represents an optional double bond; YA is xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94C(xe2x95x90O)NHxe2x80x94; or xe2x80x94C(xe2x95x90O)N(CH3)xe2x80x94; YB is a member selected from the group consisting essentially of a direct single bond; a direct double bond; xe2x80x94CH2xe2x80x94; xe2x80x94CH2CH2xe2x80x94; xe2x80x94CH2CH2CH2xe2x80x94; xe2x95x90CHxe2x80x94; xe2x95x90CHCH2xe2x80x94; xe2x95x90CHCH2CH2CH2, xe2x95x90CHCH2CH2CH2CH2xe2x80x94; and xe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94; and YC is a member selected from the group consisting essentially of cyclohexyl; phenyl substituted by 0 to 3 R20 where R20 is a member selected from the group consisting essentially of methyl, methoxy, hydroxy, benzyloxy, and nitro; pyridyl; 1-naphthyl; 2-naphthyl.
(II) Bioisostere Replacement Compounds Active As Adrenergic xcex11-Antagonists and xcex21-Agonists
The subject matter of the present invention relates to all and every indazole-for-catechol bioisostere replacement involving adrenergic receptor agonists and antagonists, and particularly the xcex11-antagonist and xcex21-agonist classes of adrenergic agents which have a catechol moiety as a central and characteristic portion of their overall chemical structure. The present invention relates to both novel indazole compounds resulting from the indazole-for-catechol bioisostere replacement, as well as to the replacements as a general class or genus of chemical compounds. The present invention further relates to the corresponding therapeutic methods of treatment which utilize said novel indazole compounds as the active therapeutic agent, and to the corresponding pharmaceutical compositions which utilize said novel indazole compounds as the active ingredient therein.
The present invention relates in particular to indazole-for-catechol bioisostere replacements active as adrenergic xcex11-antagonists and xcex21-agonists, comprising a compound of Formulas (6.22) or (6.23):
(II) 
wherein
RC2 and RA2 and RB2 are defined the same as RC1 and RA1 and RB1 herein under Formulas (5.10) and (5.11), but are selected on an independent basis therefrom; and
R2a and R2b are each individually and independently a member selected from the group consisting essentially of hydrogen and the substituents defined by partial Formulas (6.24), (6.26), (6.41), (6.43), (6.48), and (6.50) below, provided that both of R2a and R2b cannot be hydrogen at the same time;
wherein preferred embodiments comprise compounds where one of R2a and R2b is independently selected as hydrogen; and
wherein said substituents in addition to hydrogen which define each of R2a and R2b comprise a member independently selected from the group consisting essentially of the moieties of partial Formulas (6.24), (6.26), (6.41), (6.43), (6.48), and (6.50):
(II-A) 
wherein the dashed line represents an optional double bond; R23 is a member selected from the group consisting essentially of hydrogen; (C1-C4) alkyl, (C2-C4) alkenyl, and phenyl(C1-C4) alkyl-, where said alkyl, alkenyl, and phenyl or alkyl group attached thereto are substituted by 0 to 3 substituents R5, where the substituent R5 is as defined herein, but independently selected therefrom; and R24 is a member selected from the group consisting essentially of hydrogen and (C1-C4) alkoxy;
(II-B) R2a and R2b are taken together to form the moiety of partial Formula (6.26): 
wherein E represents N, resulting in a pyrimidinyl moiety and overall a quinazoline series of compounds; or represents CH, resulting in a pyridyl moiety and overall a quinoline series of compounds; R25 and R26 are each a member independently selected from the group consisting essentially of hydrogen; (C1-C6) alkyl (C2-C6) alkenyl; (C3-C8) cycloalkyl; hydroxy(C1-C6) alkyl; phenyl; benzyl; phenylethyl; and 2-furfuryl; and
R27 is independently selected from the group consisting essentially of:
(II-C) 
wherein m is an integer independently selected from 2 and 3 in each instance of its occurrence; n is an integer selected from 2, 3, and 4; p is an integer selected from 2 and 3; and n and p together represent a total which is an integer selected from 5, 6, and 7;
(II-D) 
wherein R47 is a member independently selected from the group consisting essentially of:
(a) (C1-C4) alkyl optionally substituted by 1 or 2 hydroxyl groups; phenyl(C1-C4) alkyl- optionally substituted on the phenyl portion thereof by 1 or 2 hydroxyl groups; and cinnamyl;
(b) xe2x80x94CH2C(xe2x95x90O)NHR48 where R48 is a member independently selected from the group consisting essentially of (C1-C4) alkyl; and phenyl optionally substituted by (C1-C4) alkoxy, trifluoromethyl, fluoro, bromo, or chloro;
(c) xe2x80x94CH2C(xe2x95x90O)NHR49R50 where R49 and R50 are each defined the same as R48; but are selected on an independent basis therefrom;
(d) a radical of partial Formula (6.44): 
wherein the nitrogen atom forms part of a heterocyclic radical selected from the group consisting essentially of morpholino; hexamethylene-imino; and pyrrolidino; and
(e) xe2x80x94CH2C(xe2x95x90O)OR51 where R51 is hydrogen or (C1-C4) alkyl;
(II-E) 
wherein RC2 is a member independently selected from the group consisting essentially of hydrogen; hydroxy; and xe2x80x94Oxe2x80x94(C1-C4) alkyl, in accordance with whether an inclusionary or exclusionary bioisostere is intended; and R54a and R54b are independently selected from the group consisting essentially of CnH2n+1 where n is an integer selected from 1, 2, 3, and 4; and
(II-F) 
wherein
R57 is a member independently selected from the group consisting essentially of hydrogen; (C1-C2) alkyl; and hydroxy;
R58 is a member independently selected from the group consisting essentially of hydrogen; and (C1-C2) alkyl;
W is xe2x80x94C(R64)(R65)xe2x80x94; xe2x80x94CH(R64)CH(R65)xe2x80x94; or xe2x80x94CH(R64)CH(R65)CH2xe2x80x94, where R64 is a member independently selected from the group consisting essentially of hydrogen and methyl; and R65 is a member independently selected from the group consisting essentially of hydrogen, methyl, and hydroxy;
R59 is a member selected independently from the group consisting essentially of hydrogen; methyl; phenyl; and benzoyl; where said phenyl and benzoyl groups are optionally substituted by a member independently selected from the group consisting essentially of m-hydroxy; p-hydroxy; m- and p-dihydroxy; m-(C1-C2) alkyl; (C1-C3) alkoxy; fluoro; chloro; cyano; hydroxymethyl; acetyl; and o-allyl; and
R60 is a member independently selected from the group consisting essentially of hydrogen; and methyl.
(III) Bioisostere Replacement Compounds Active As Calcium Channel Antagonists
The present invention relates to the discovery that the indazole nucleus is a moiety which is capable of being an bioisostere replacement for the catechol moiety where it is an essential part of numerous endogenous ligands acting on important calcium channel receptors and thereby carrying out essential metabolic, especially cardiovascular functions in the body. Calcium channel antagonists, particularly those of the verapamil, type have such a catechol moiety as a central and characteristic portion of their overall chemical structure, and they are therapeutically useful in the area of antihypertensive treatment, and in the cardiovascular field they are especially useful, often having activity as antianginal and antiarrhythmic agents in addtion to their antihypertensive utility.
In accordance with the present invention the indazole nucleus is a biobioisostere replacement for the catechol moiety which is an essential part of calcium channel antagonists including especially verapamil, which have been and in the future will be created and developed for therapeutic treatments, as detailed further herein. The present invention relates to both novel indazole compounds resulting from the indazole-for-catechol bioisostere replacement in such calcium channel antagonists, as well as to the replacements as a general class or genus of chemical compounds. The present invention further relates to the corresponding therapeutic methods of treatment which utilize said novel indazole compounds as the active therapeutic agent, and to the corresponding pharmaceutical compositions which utilize said novel indazole compounds as the active ingredient therein.
In a preferred embodiment, the present invention relates in particular to indazole-for-catechol bioisostere replacements active as calcium channel antagonists, and in particular to those relating to verapamil and verapamil types of compounds, comprising a compound of Formulas (7.22) or (7.23):
(III) 
wherein
RC3 and RA3 and RB3 are defined the same as RC1 and RA1 and RB1 herein under Formulas (5.10) and (5.11), but are selected on an independent basis therefrom; and
R3a and R3b are each individually and independently a member selected from the group consisting essentially of hydrogen and the substituents defined by partial Formulas (7.25); (7.28); (7.35); and (7.41) below, provided that both of R3a and R3b cannot be hydrogen at the same time;
wherein preferred embodiments comprise compounds where one of R3a and R3b is independently selected as hydrogen; and
wherein said substituents in addition to hydrogen which define each of R3a and R3b comprise a member independently selected from the group consisting essentially of the moieties of partial Formulas (7.24); (7.25); (7.28); (7.35); and (7.41):
(III-A) 
wherein R70 is a member independently selected from the group consisting essentially of hydrogen; (C1-C4) alkyl; phenyl; benzyl; and cyclohexyl; R71 is a member independently selected from the group consisting essentially of (C1-C4) alkyl; n is an integer independently selected from 2, 3, and 4; and m is an integer independently selected from 1, 2, and 3;
(III-B) 
wherein R73 is a member independently selected from the group consisting essentially of hydrogen and (C1-C4) alkyl; R74 is a member independently selected from the group consisting essentially of a single bond and a linear- or branched-alkylene radical (C1-C5) alkyl; W1 is a member independently selected from the group consisting essentially of straight- and branched-alkylene radicals (C2-C5) alkyl, and 2-hydroxypropylene; R75 and R76 are members independently selected from the group consisting essentially of hydrogen, methyl, ethyl, chloro, and bromo, W2 is a member independently selected from the group consisting essentially of xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, and xe2x80x94SO2xe2x80x94; and A is a member indpendently selected from the group consisting essentially of
(a) 
wherein R77 and R78 are taken together with the carbon atom to which they are attached to form an optionally aromatic mono- or di-cyclic carbocyclic group having from 5 to 10 carbon atoms and optionally substituted in the xcex1-position with respect to the methylene group of partial Formula (7.29) by R84 as defined below; an optionally aromatic 5-membered heterocyclic group where the heteroatoms or hetero groups are members independently selected from the group consisting essentially of O, S, N, xe2x80x94N(R79)xe2x80x94, O together with N, O together with xe2x80x94N(R79)xe2x80x94, S together with N, S together with xe2x80x94N(R79)xe2x80x94, N together with N, and N together with xe2x80x94N(R79)xe2x80x94, optionally substituted in the ca-position with respect to the methylene group of partial Formula (7.29) by R84 as defined below, where R79 is hydrogen, (C1-C4) alkyl, or phenyl; or an optionally aromatic 6- to 10-membered mono- or di-cyclic heterocyclic group, where the heteroatoms or heterogroups are members independently selected from the group consisting essentially of O, S, N, xe2x80x94N(R79)xe2x80x94, O together with N, O together with xe2x80x94N(R79)xe2x80x94, S together with N, S together with xe2x80x94N(R79)xe2x80x94, N together with N, and N together with xe2x80x94N(R79)xe2x80x94, optionally substituted in the xcex1-position with respect to the methylene group of partial Formula (7.29) by R84 as defined below, where R79 is hydrogen, (C1-C4) alkyl, or phenyl;
(b) 
xe2x80x83wherein
R80 and R81 are members independently selected from the group consisting essentially of hydrogen; (C1-C4) alkyl; phenyl; and taken together with the carbon atom to which they are attached represent an optionally aromatic 6-membered carbocyclic ring; R82 is O or S; R83 is O; S; or xe2x80x94N(R79)xe2x80x94; R84 is a member independently selected from the group consisting essentially of hydrogen; (C1-C4) alkyl; (C3-C7) cycloalkyl; benzyl; and phenyl optionally substituted with 1 to 3 substituents selected from the group consisting essentially of fluoro, chloro, bromo, (C1-C4) alkyl, (C1-C4) alkoxy, and nitro; and R85 and R86 are members independently selected from the group consisting essentially of hydrogen; (C1-C4) alkyl; and benzoyl;
(III-C) 
wherein R88 is hydrogen or a group of partial Formula (7.36): 
where R89 is hydrogen or fluorine;
(III-D)
R3a and R3b are taken together to form the moiety of partial Formula (7.41): 
wherein A is xe2x80x94CH2CH2xe2x80x94; xe2x80x94CHxe2x95x90CHxe2x80x94; xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94; or xe2x80x94C(R94)xe2x95x90Nxe2x80x94 where R94 is (C1-C3) alkyl; and B is methylene; carbonyl; or thiocarbonyl; or A is xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94Nxe2x95x90CHxe2x80x94; xe2x80x94CH(OH)xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94; xe2x80x94C(xe2x95x90NOH)xe2x80x94C(xe2x95x90O)xe2x80x94; or xe2x80x94CH(NHR95)xe2x80x94C(xe2x95x90O)xe2x80x94, where R95 is hydrogen or (C1-C3) alkyl substituted by phenyl, methoxyphenyl, or dimethoxyphenyl; and B is methylene; E is a member independently selected from the group consisting essentially of n-(C2-C4) alkylene, optionally substituted by (C1-C3) alkyl, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene; G is a member independently selected from the group consisting essentially of n-(C1-C5) alkylene, optionally substituted by (C1-C3) alkyl, where one methylene group of an n-alkylene of 2 to 5 carbon atoms may be replaced by a carbonyl group, with the proviso that B represents a methylene or carbonyl group, or methylene-n-hydroxyalkylene of 1 to 4 carbon atoms, where the methylene group is attached to the nitrogen atom; R90 is a member independently selected from the group consisting essentially of hydrogen; (C1-C3) alkyl; phenyl(C1-C3) alkyl; (C1-C3) alkanoyl; (C1-C3) alkoxycarbonyl; and (C3-C5) alkenyl; and R91, R92, and R93 are each a member independently selected from the group consisting essentially of hydrogen; fluorine; chlorine; bromine; hydroxy; cyano; nitro; trifluoromethyl (C1-C4) alkyl; (C1-C4) alkoxy; (C1-C3) alkylamino; di(C1-C3) alkylamino; (C1-C3) alkanoylamino; (C1-C3) alkoxycarbonylamino; bis(C1-C3) alkoxycarbonylamino; (trifluoromethyl)methylamino; and (trifluoromethyl)ethylamino; and R91 and R92 taken together with each other are (C1-C2) alkylenedixoy.
(IV) Bioisostere Replacement Compounds Active As Antineoplastic Agents
Antineoplastic agents in which bioisosteric replacement of indazole-for-catechol may be carried out in accordance with the present invention are described herein. An example of the catechol-containing antineoplastic agents and their derivatives which have a catechol moiety which may be replaced with the indazole bioisostere moiety while maintaining or improving the biological property of the catechol containing predecessor compound, is trimetrexate. The manner in which such a bioisostere replacement is constructed is illustrated in Formulas (8.0), (8.1), and (8.2): 
The indazole nucleus is capable of being a bioisostere replacement for the catechol moiety where it is an essential part of numerous endogenous ligands acting on important receptors and signal transduction pathways which are essential to the unwanted proliferation of many types of tissue, including especially neoplasms and psoriasis, a non-neoplastic disease of the skin characterized by abnormally rapid proliferation of epidermal cells. Antineoplastic agents, especially trimetrexate and protein tyrosine kinase inhibitors, particularly those of the 4-anilino-quinazoline type, have such a catechol moiety as a central and characteristic portion of their overall chemical structure, and they are therapeutically useful in the area of antineoplastic treatment, as well as in the treatment of hyperproliferative conditions such as psoriasis.
In accordance with the present invention the indazole nucleus is a biobioisostere replacement for the catechol moiety which is an essential part of antineoplastic and antiproliferative agents, including especially trimetrexate, and 4-anilino-quinazolines such as PD-153,035; CP-292,597; CP-358,774; and ZD-1839, which have been and in the future will be created and developed for therapeutic treatments, as detailed further herein. The present invention relates to both novel indazole compounds resulting from the indazole-for-catechol bioisostere replacement in such antineoplastic and antiproliferative agents, as well as to the replacements as a general class or genus of chemical compounds. The present invention further relates to the corresponding therapeutic methods of treatment which utilize said novel indazole compounds as the active therapeutic agent, and to the corresponding pharmaceutical compositions which utilize said novel indazole compounds as the active ingredient therein.
The present invention relates in particular to indazole-for-catechol bioisostere replacements active as antineoplastic and antiproliferative agents, and in particular to those relating to trimetrexate, and 4-anilino-quinazolines such as PD-153,035; CP-292,597; CP-358,774; and ZD-1839, comprising a compound of Formulas (8.21) or (8.22):
(IV) 
wherein
RC4 and RA4 and RB4 are defined the same as RC1 and RA1 and RB1 herein under Formulas (5.10) and (5.11), including preferred embodiments thereof, but are selected on an independent basis therefrom; and
R4a and R4b are each individually and independently a member selected from the group consisting essentially of hydrogen and the substituents defined by partial Formulas (8.23); (8.28); (8.40); and (8.45) below, provided that both of R4a and R4b cannot be hydrogen at the same time;
wherein preferred embodiments comprise compounds where one of R4a and R4b is independently selected as hydrogen; and
wherein said substituents in addition to hydrogen which define each of R4a and R4b comprise a member independently selected from the group consisting essentially of the moieties of partial Formulas (8.23); (8.28); (8.40); and (8.45):
(IV-A) 
wherein Z is 2-hydroxyethanesulfonic acid or glucuronic acid, as well as pharmaceutically acceptable prodrugs and metabolites thereof;
(IV-B) R4a and R4b are taken together to form the moiety of partial Formula (8.28): 
wherein Ar a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of from 5 to 12 atoms where each monocyclic ring may contain 0 to 3 heteroatoms, and each bicyclic ring may contain 0 to 4 heteroatoms selected from N, O, and S, provided said heteroatoms are not vicinal oxygen and/or sulfur atoms; W4 is a member independently selected from the group consisting essentially of a bond; xe2x80x94Oxe2x80x94; xe2x80x94Sxe2x80x94; xe2x80x94S(xe2x95x90O)xe2x80x94; xe2x80x94S(xe2x95x90O)2xe2x80x94; xe2x80x94OCH2xe2x80x94; xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94; xe2x80x94C(xe2x95x90S)xe2x80x94; xe2x80x94SCH2xe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94NHCH2xe2x80x94; xe2x80x94NHCH(R97)xe2x80x94, xe2x80x94N(R97)xe2x80x94 or xe2x80x94N(R97)CH2xe2x80x94 where R97 is (C1-C4) alkyl; xe2x80x94CH2xe2x80x94CH2xe2x80x94, and xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94; m is an integer selected from 0, 1, 2, and 3; and R96 is a member independently selected from the group consisting essentially of hydrogen; xe2x80x94(C1-C4) alkyl; xe2x80x94(C2-C4) alkenyl; -phenyl; phenyl(C1-C3) alkyl-; phenyl(C2-C3) alkenyl-; -hydroxy; hydroxy(C1-C4) alkyl-; xe2x80x94(C1-C4) alkoxy; (C1-C3) alkoxy(C1-C2) alkyl-; phenyl(C1-C3) alkoxy-; phenyloxy-; (C1-C4) alkylcarbonyloxy-; phenylcarbonyloxy-; bromo, chloro, or fluoro; (bromo, chloro, or fluoro)(C1-C3) alky-; -nitro; -cyano; -amino; mono- or di-(C1-C4) alkylamino-; (C1-C4) alkylcarbonylamino-; phenylcarbonylamino-; -carboxy; carboxy(C1-C3) alkyl-; (C1-C3) alkoxycarbonyl-; phenyl(C1-C3) alkoxycarbonyl; (C1-C3) alkoxycarbonyl(C1-C3) alkyl-; amino(C1-C3) alkoxy-; amido; mono- and di-(C1-C3) alkylamido; N,Nxe2x80x94(C1-C3) cycloalkylamido-; (C1-C3) alkylthio-; (C1-C3) alkylsulfinyl-; -sulfonyl; mono- and di-(C1-C3) alkylsulfonyl-; -sulfamoyl; mono- and di-(C1-C3) alkylsulfamoyl-; (bromo, chloro, or fluoro)phenyl-; benzoyl; and provided that m is 1, azido and R94a-ethynyl, where R94a is hydrogen or (C1-C6)alkyl substituted by 0 to 2 substituents where said substituent is a member independently selected from the group consisting essentially of hydrogen; amino; hydroxy; R94bxe2x80x94O; R94bxe2x80x94NH; and (R94b)2xe2x80x94N, where R94b is (C1-C4) alkyl;
(IV-C) 
wherein Z is a moiety of partial Formulas (8.41) and (8.42): 
wherein m is an integer selected from 0, 1, 2, 3, and 4; n is an integer selected from 0, 1, and 2; D is saturated carbon; oxy; or thio; R105 is a member independently selected, for each occurrence in partial Formulas (8.41) and (8.42), from the group consisting essentially of mono-, di-, or tri-fluoromethyl; bromo, chloro, or fluoro; nitro; hydroxy; amino; azido; isothiocyano; (C1-C4) alkyl; phenyl; thienyl; (C1-C4) alkoxy; benzyloxy; phenoxy; (C2-C6) alkenyl; (C2-C6) alkynyl; (C1-C4) alkylenedioxy; cyano; benzoylamino; trifluoromethylcarbonylamino; (C1-C4) alkanoylamino; (C1-C4) alkanoyl-N-mono- or xe2x80x94N,N-di-(C1-C4) alkylamino; (C1-C4) alkylsulfonylamino; trifluoromethylsulfonylamino; (C1-C4) alkylthio; (C1-C4) alkylsulfinyl; (C1-C4) alkylsulfonyl; pyrrol-1-yl; piperidin-1-yl; and pyrrolidin-1-yl; where said phenyl, benzyloxy, phenoxy and benzoylamino groups are optionally mono-substituted with a member independently selected from the group consising essentially of bromo, chloro, or fluoro; nitro; trifluoromethyl; hydoxy; and (C1-C4) alkyl; and where said (C1-C4) alkylenedioxy is linked at both ends thereof to adjacent carbons of the benzene moiety to which it is attached; R106, when it is not attached to a ring carbon which is adjacent to an oxy, thio or xe2x80x94Nxe2x80x94 ring atom, is a member independently selected, for each occurrence in partial Formulas (8.41) and (8.42), from the group consisting essentially of hydroxy; amino; N-mono- or N,N-di-(C1-C4) alkylamino; sulfo; and (C1-C4) alkoxy; and R106, when it is attached to a ring carbon which is adjacent to an oxy, thio or xe2x80x94Nxe2x80x94 ring atom, is a member independently selected, for each occurrence in partial Formulas (8.41) and (8.42), from the group consisting essentially of carboxy; hydroxy(C1-C4) alkyl; (C1-C4) alkoxy(C1-C4) alkyl; amino(C1-C4) alkyl; mono-Nxe2x80x94 and di-N,Nxe2x80x94(C1-C4) alkylamino(C1-C4) alkyl; morpholino(C1-C4) alkyl; 4-(C1-C4) alkyl-piperazin-1-yl(C1-C4) alkyl; carboxy(C1-C4) alkyl; (C1-C4) alkoxycarbonyl; sulfo(C1-C4) alkyl; and (C1-C4) alkyl;
(IV-D) R4a and R4b are taken together to form the moiety of partial Formula (8.45): 
wherein R96 and m are as defined under (IV-C) above, but are selected on an independent basis therefrom; W5 is xe2x80x94Yxe2x80x94CH2xe2x80x94; xe2x80x94CH2xe2x80x94Yxe2x80x94; or xe2x80x94Yxe2x80x94; where Y is O, S(O)q where q is an integer selected from 0, 1, and 2, or NR100 where R100 is hydrogen or (C1-C8) alkyl; and R99 is a group xe2x80x94ZR101xe2x80x94 where Z is joined to R101 through a bridging group (CH2)p where p is an integer selected from 0, 1 and 2; and Z is a member independently selected from the group consisting essentially of xe2x80x94Vxe2x80x94CH2xe2x80x94, xe2x80x94Vxe2x80x94CF2xe2x80x94, xe2x80x94CH2xe2x80x94Vxe2x80x94, xe2x80x94CF2xe2x80x94Vxe2x80x94, and xe2x80x94Vxe2x80x94, where V is a hydrocarbyl group containing 0, 1, or 2 carbon atoms; carbonyl; xe2x80x94CH(OH)xe2x80x94; sulfonamide; amide; xe2x80x94Oxe2x80x94; xe2x80x94S(O)qxe2x80x94; and xe2x80x94NR102 where R102 is hydrogen or (C1-C4) alkyl; and R101 is optionally substituted (C3-C7) cycloalkyl; or an optionally substituted 5,6,7,8,9, or 10-membered carbocyclic or heterocyclic moiety where said carbocyclic moiety is a member independently selected from the group consisting essentially of phenyl; benzyl; indene; naphthalene; tetralin; decalin; cyclopentyl; cyclohexyl; and cycloheptyl; and said heterocyclic moiety is a member independently selected from the group consisting essentially of furan; dioxolane; thiophene; pyrrole; imidazole; pyrrolidine; pyran; pyridine; pyrimidine; morpholine; piperidine; oxazoline; oxazolidine; thiazole; thiadiazole; benzofuran; indole; isoindole; quinazoline; quinoline; and isoquinoline; or R99 is a group xe2x80x94ZR101xe2x80x94 where Z is xe2x80x94NR102, and xe2x80x94NR102 and R101 together form a 5, 6, 7, 8, 9, or 10-membered heterocyclic moiety as defined under R101 above.
(V) Bioisostere Replacement Compounds Active As PDE4 Inhibitors
This particular embodiment of the present invention relates to compounds having therapeutic usefulness based on their activity as phosphodiesterase-4 inhibitors, comprising an indazole-for-catechol bioisosteric replacement wherein said therapeutic usefulness is equivalent to or an improvement over the same activity possessed by the corresponding catechol-containing predecessor compound. In a preferred embodiment of this aspect of the present invention, the indazole-for-catechol bioisostere replacement compounds are therapeutically useful in treating asthma.
The indazole replacement bioisostere compounds of the present invention are useful in treating or preventing one or members selected from the groups of diseases and conditions consisting essentially of (1) inflammatory comprising: joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis, and Crohn""s disease; (2) respiratory comprising: acute respiratory distress syndrome, bronchitis, chronic obstructive pulmonary disease (COPD), including asthma, chronic bronchitis and pulmonary emphysema; and silicosis; (3) infectious comprising: sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, fever and myalgias due to bacterial, viral or fungal infection, and influenza; (4) immune comprising: autoimmune diabetes, systemic lupus erythematosis, graft vs. host reaction, allograft rejections, multiple sclerosis, psoriasis, and allergic rhinitis; and (5) general comprising: bone resorption diseases; reperfusion injury; cachexia secondary to infection or malignancy; cachexia secondary to human acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV) infectioin, or AIDS related complex (ARC); keloid formation; scar tissue formation; type 1 diabetes mellitus; and leukemia; wherein said compounds are inhibitors of phosphodiesterase isozyme 4 (PDE4).
A further embodiment of the present invention relates in particular to indazole-for-catechol bioisostere replacements active as PDE4 inhibitors, especially inhibitors useful in treating asthma and other respiratory and inflammatory diseases and conditions, comprising a compound of Formulas (9.0) and (9.1):
(V) 
and pharmaceutically acceptable salts thereof, wherein:
RC5 is a member independently selected from the group consisting essentially of hydrogen; hydroxy; xe2x80x94Oxe2x80x94(C1-C4) alkyl xe2x80x94Oxe2x80x94(C1-C4) alkyl(C1-C2) alkoxy; and xe2x80x94Oxe2x80x94(C1-C4) alkyl-morpholino;
RA5 is a member independently selected from the group consisting essentially of hydrogen, (C1-C9) alkyl; xe2x80x94(CH2)n(C3-C10) cycloalkyl wherein n is an integer selected from 0, 1, and 2; (C1-C6) alkoxy(C1-C6) alkyl; (C2-C6) alkenyl; xe2x80x94(CH2)n(C3-C9) heterocyclyl wherein n is selected from 0, 1, and 2; and xe2x80x94(Z1)b(Z2)c(C6-C10) aryl wherein b and c are integers independently selected from 0 and 1, Z1 is (C1-C6) alkylene or (C2-C6) alkenylene, and Z2 is O, S, SO2, or NR119; and further wherein said heterocyclyl is a member independently selected from the group consisting essentially of acridinyl; benzimidazolyl; benzodioxolane; 1,3-benzodioxol-5-yl; benzo[b]furanyl; benzo[b]thiophenyl; benzoxazolyl; benzthiazolyl; carbazolyl; cinnolinyl; 2,3-dihydrobenzofuranyl; 1,3-dioxane; 1,3-dioxolane; 1,3-dithiane; 1,3-dithiolane; furanyl; imidazolidinyl; imidazolinyl; imidazolyl; 1H-indazolyl; indolinyl; indolyl; 3H-indolyl; isoindolyl; isoquinolinyl; isothiazolyl; isoxazolyl; morpholinyl; 1,8-naphthyridinyl; oxadiazolyl; 1,3-oxathiolane; oxazolidinyl; oxazolyl; oxiranyl; parathiazinyl; phenazinyl; phenothiazinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; pteridinyl; pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolo[1,5-c]triazinyl; pyrazolyi; pyridazinyl; pyridyl; pyrimidinyl; pyrimidyl; pyrrolyl; pyrrolidinyl; purinyl; quinazolinyl; quinolinyl; 4H-quinolizinyl; quinoxalinyl; tetrazolidinyl; tetrazolyl; thiadiazolyl; thiazolidinyl; thiazolyl; thienyl; thiomorpholinyl; triazinyl; and triazolyl; wherein said aryl is a carbocyclic moiety which is a member independently selected from the group consisting essentially of benzyl; cis- and trans-decahydronaphthalenyl; 2,3-1H-dihydroindenyl (indanyl); indenyl; 1-naphthalenyl; 2-naphthalenyl; phenyl; and 1,2,3,4-tetrahydronaphthalenyl; wherein said alkyl, alkenyl, alkoxyalkyl, heterocyclyl, and aryl moieties defining said RA5 groups are substituted by 0 to 3 substituents where each said substituent comprises a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; hydroxy; (C1-C5) alkyl; (C2-C5) alkenyl; (C1-C5) alkoxy; (C3-C6) cycloalkoxy; mono-, di-, and tri-fluoromethyl; nitro; xe2x80x94C(xe2x95x90O)OR119, xe2x80x94C(xe2x95x90O)NR119R120, xe2x80x94NR119R120 and xe2x80x94S(xe2x95x90O)2NR119R120;
RB5 is a member independently selected from the group consisting essentially of hydrogen; (C1-C9) alkyl; (C2-C3) alkenyl; phenyl; (C3-C7) cycloalkyl; and (C3-C7) cycloalkyl(C1-C2) alkyl; wherein said alkyl, alkenyl and phenyl moieties defining said R85 groups are substituted by 0 to 3 substituents where each said substituent comprises a member independently selected from the group consisting essentially of methyl; ethyl; mono-, di-, and tri-fluoromethyl; and bromo, chloro, or fluoro;
R5a and R5b are independently selected from the group consisting essentially of hydrogen and hereinafter recited substituents, provided that one, but not both of R5a and R5b must be independently selected as hydrogen, wherein said substituents comprise moieities of partial Formulas (V-A)xe2x80x94(9.2)-(9.5); (V-B)xe2x80x94(9.6)-(9.14); (V-C)xe2x80x94(9.16)-(9.35); (V-D)xe2x80x94(9.36); and (V-E)xe2x80x94(9.37)-(9.49):
(V-A) 
or, said substituents defining R5a and R5b comprise:
(V-B)
a member selected from the group consisting essentially of R229; xe2x80x94C(xe2x95x90O)NR222(CHR222)mC(xe2x95x90O)NR222O(CH2)q(C6-C10)aryl); xe2x80x94C(xe2x95x90NR242)NH(CH2)p(C6-C10) aryl; xe2x80x94C(xe2x95x90O)NR218(CHR222)mC(xe2x95x90O)NR222(CH2)pOR222; xe2x80x94C(xe2x95x90O)NR222(CHR222)mS(C1-C4) alkyl; xe2x80x94C[xe2x95x90NOC(xe2x95x90O)R235]R236; xe2x80x94CR227R228CHR238NR219SO2(CH2)pA; xe2x80x94CR227R228CHR238NR219P(xe2x95x90O)(OR222)C(xe2x95x90O)(C1-C4) alkyl; xe2x80x94CR227R238CHR238NR219P(xe2x95x90O)[(C1C4) alkoxy]2, xe2x80x94Z3xe2x80x94R217; and xe2x80x94(CR227R228)mNR219(C(O))qR220 wherein p is an integer selected from 0, 1, and 2; m is an integer selected from 1, 2, 3, 4, 5, and 6; and q is an integer selected from 1 and 2;
or, said substituents defining R5a and R5b comprise:
a moiety of partial Formulas (9.6) through (9.14), inclusive: 
(V-C)
or, said substituents defining R5a and R5b comprise:
a member independently selected from the group consisting essentially of 2-oxo-4-pyrrolyl; pyrazolyl; 2-oxo-3,4-dihydro-5-pyrimidyl; 2-oxo-3,4-dihydro-4-pyrimidyl; 2-oxo-tetrahydro-4-pyrimidyl; 2-oxo-tetrahyro-5-pyrimidyl; 2-oxo-4-pyrimidyl; and 2-oxo-5-pyrimidyl; wherein each of said R2a and R2b groups is substituted by 0, 1, 2, 3, or 4 R236 groups;
or, said substituents defining R5a and R5b comprise:
a moiety of partial Formulas (9.16) through (9.35), inclusive: 
(V-D)
or, said substituents defining R5a and R5b comprise:
a moiety of partial Formula (9.36): 
xe2x80x83wherein
the broken line indicates a single or double bond;
X1 is xe2x80x94CR472R473xe2x80x94 where said broken line indicates a single bond; or xe2x80x94CR473xe2x80x94 where said broken line indicates a double bond;
X2 is xe2x80x94CR475R477R478xe2x80x94 or xe2x80x94C(xe2x95x90NOR481)R482xe2x80x94 where said broken line indicates a single bond; or xe2x80x94CR477R478 where said broken line indicates a double bond;
R472 is a member independently selected from the group consisting essentially of H; hydroxy; bromo, chloro, or fluoro; and xe2x80x94OR479;
each R473 is a member independently selected from the group consisting essentially of cyano; cyanomethyl; benzyioxy; xe2x80x94R475; xe2x80x94CO2R475; xe2x80x94CO2(CH2)n(C6-C10) aryl; xe2x80x94C(Y)NR475R476; xe2x80x94C(Y)NR475(CH2)n(C6-C10) aryl; xe2x80x94(CH2)n(C6-C10) aryl; and xe2x80x94(CH2)n(5- to 10-membered heteroaryl); where n is an integer selected from 0, 1, 2, and 3; each R473 group is substituted by 0 to 3 substituents R474; and each R473 group is substituted by 0 or 1 substituent R480;
each R474 is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; cyano; nitro; (C1-C6) alkyl; (C2-C6) alkenyl; xe2x80x94OR475; (C3-C7) cycloalkoxy; NR475R476; xe2x80x94NR475OR476; xe2x80x94S(O)mR475 where m is an integer selected from 0, 1, and 2; xe2x80x94CO2R475, xe2x80x94C(xe2x95x90O)R475; xe2x80x94SO2NR475R476; xe2x80x94C(xe2x95x90O)NR475R476; xe2x80x94CR475R476SO2NR475R476; xe2x80x94CR475R476C(xe2x95x90O)NR475R476; xe2x80x94NHSO2R475; xe2x80x94NHSO2NR475R476; xe2x80x94NHC(xe2x95x90O)NR475R476; xe2x80x94NHC(xe2x95x90O)(C1-C6) alkyl; and xe2x80x94NHC(xe2x95x90O)O(C1-C6) alkyl);
each R475 and R476 is a member independently selected from the group consisting essentially of H; and (C1-C6) alkyl;
R477 is a member independently selected from the group consisting essentially of xe2x80x94R473; 2-oxo-pyridyl; 3-oxo-pyridyl; 4-oxo-pyridyl; 2-oxo-pyrrolyl; 4-oxo-thiazolyl; 4-oxo-piperidyl; 2-oxo-quinolyl; 4-oxo-quinolyl; 1-oxo-isoquinolyl; 4-oxo-oxazolyl; 5-oxo-pyrazolyl; 5-oxo-isoxazolyl; and 4-oxo-isoxazolyl; where each of said R477 groups is substituted by 0 to 3 substituents R474;
R478 is a member independently selected from the group consisting essentially of xe2x80x94R475; cyano; xe2x80x94(CH2)p(C6-C10) aryl; and xe2x80x94(CH2)p(5- to 10-membered heteroaryl); where p is an integer selected from 1, 2, and 3; and where each said R478 group is substituted by 0 to 3 substituents R474;
R479 is a member independently selected from the group consisting essentially of formyl; carbamoyl; thiocarbamyl; (C1-C6) alkyl; (C2-C6) alkenyl; (C1-C4) alkoxy(C1-C4) alkyl-; and (C1-C6) alkanoyl; where said alkyl moieties of each of said R479 groups is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; hydroxy; and (C1-C4) alkoxy;
R480 is a member independently selected from the group consisting essentially of cyclobutyl; cyclopentyl; cyclohexyl; 2-cyclobuten-1-yl; 2-cyclopenten-1-yl; 3-cyclopenten-1-yl; 2,4-cyclopentadien-1-yl; 3,5-cyclohexadien-1-yl; pyrrolyl; pyrrolidinyl; dioxolanyl; imidazolyl; oxazolyl; imidazolidinyl; pyrazolyl; pyrazolidinyl; pyranyl; piperidinyl; 1,4-dioxanyl; morpholinyl; 1,4-dithianyl; thiomorpholinyl; piperazinyl; 1,3,5-trithianyl; oxazinyl; isoxazinyl; oxathiazinyl; and oxadiazinyl; where each of said R480 groups is substituted by 0 to 2 (C1-C2) alkyl;
R481 is a member independently selected from the group consisting essentially of H; (C1-C6) alkyl; (C2-C6) alkenyl; (C2-C6) alkynyl; xe2x80x94C(Y)NR475R476; xe2x80x94C(Y)NH(C6-C10) aryl; xe2x80x94C(Y)(C1-C6) alkoxy; xe2x80x94C(Y)(C6-C10) aryloxy; and xe2x80x94C(Y)(C1-C6) alkyl);
R482 is a member independently selected from the group consisting essentially of phenyl and pyridinyl; where each of said R482 groups is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; (C1-C4) alkyl; hydroxy; (C1-C4) alkoxy; xe2x80x94NR475R476; and xe2x80x94S(O)mR475, where m is an integer selected from 0, 1, and 2; and,
Y is O or S; or
or, said substituents defining R5a and R5b comprise:
a moiety of partial Formulas (9.37) through (9.49), inclusive:
(V-E) 
(I) Bioisostere Replacement Compounds Active As Cholinesterase Inhibitors
There are several important therapeutic classes of cholinergic antagonists, especially cholinesterase inhibitor which have a catechol moiety as a central and characteristic portion of their overall chemical structure for which a bioisostere replacement with an indazole moiety may be carried out in accordance with the present invention, wherein the resulting indazole-containing containing compounds have the same or improved biological activity with the same or reduced undesirable side effects, as that exhibited by the catechol-containing compound.
One such important therapeutic class is that of catechol-containing cholinergic muscarinic receptor antagonists which are used as antispasmodic or spasmolytic agents such as trimebutine, trepibutone, mebeverine, and atracurium besylate, which may be represented respectively by Formulas (5.0), (5.1), (5.2), (5.3): 
All of these specific agents, and derivatives thereof, have a catechol moiety which may be replaced by an indazole moiety in accordance with the present invention.
These catechol-containing cholinergic muscarinic receptor antagonist are also useful as antiulcerative agents and include, e.g., troxipide and trithiozine, which may be represented by Formulas (5.4) and (5.5): 
These agents and derivative thereof, have a catechol moiety which may be replaced with the indazole bioisostere moiety in accordance with the present invention. The catechol-containing cholinergic muscarinic receptor antagonists further include therapeutic agents useful in ophthalmology, e.g., as mydriatic agents, which can be the subject of an indazole bioisostere replacement in accordance with the present invention.
A still further class of catechol-containing cholinergic therapeutic agents suitable for indazole bioisostere replacement comprises dopaminergic receptor antagonists such as veralipride which is useful in the treatment of menopausal disorders. Veralipride may be represented by Formula (5.6): 
An important class of catechol-containing acetylcholinesterase inhibitors are those useful in the treatment of Alzheimer""s disease, especially cognitive dysfunction associated therewith. A deficiency of structurally intact cholinergic neurons is characteristic of Alzheimer""s disease, and therapy is based on enhancing concentrations of cholinergic neurotransmitters in the central nervous system. These catechol-containing anticholinesterase agents are suitable for indazole bioisostere replacement in accordance with the present invention. For example, the agent donepezil which has a catechol-containing structure may be represented by Formula (5.7): 
In order to better understand the bioisostere replacement of the catechol moiety with an indazole moiety in accordance with the present invention, the bioisostere of donepezil in which indazole is substituted for catechol, is represented by the compounds of Formulas (5.8) and (5.9): 
Other catechol-containing anticholinesterase agents of a type similar to donepezil which are also suitable for indazole bioisostere replacement in accordance with the present invention are described in U.S. Pat. No. 4,895,841 which is incorporated herein by reference in its entirety.
The subject matter of the present invention includes within its scope all and every indazole-for-catechol bioisostere replacement relating to cholinergic antagonists and anticholinesterase agents, both as novel indazole compounds in particular and as said replacements in general. Also included within the scope of the present invention are the therapeutic methods of treatment and the pharmaceutical compositions relating thereto in which the active ingredient is an indazole-for-catechol bioisostere replacement compound, and in preferred embodiments of the present invention is as described in more detail further below.
Accordingly, the present invention relates in particular to indazole-for-catechol bioisostere replacements active as cholinergic antagonists and anticholinesterase agents, comprising a compound of Formulas (5.10) or (5.11):
(I) 
wherein
RC1 is a member independently selected from the group consisting essentially of hydrogen; hydroxy; xe2x80x94Oxe2x80x94(C1-C4) alkyl; xe2x80x94Oxe2x80x94(C1-C4) alkyl(C1-C2) alkoxy; and xe2x80x94Oxe2x80x94(C1-C4) alkyl-morpholino;
RA1 is a member independently selected from the group consisting essentially of hydrogen; (C1-C9) alkyl; xe2x80x94(CH2)n(C3-C10) cycloalkyl wherein n is 0 to 2; xe2x80x94(C1-C6) alkyl(C1-C6) alkoxy; (C2-C6) alkenyl; xe2x80x94(CH2)n(C3-C9) heterocyclyl wherein n is 0 to 2; and xe2x80x94(Zxe2x80x2)b(Zxe2x80x3)c(C6-C10) aryl wherein b and c are each independently 0 or 1, Zxe2x80x2 is (C1-C6) alkylene or (C2-C6) alkenylene, and Zxe2x80x3 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94, or xe2x80x94N(R9)xe2x80x94, and wherein said alkyl, alkenyl, alkoxyalkyl, heterocyclyl, and aryl moieties of said RA1 groups are substituted by 0 to 3 substituents independently selected from halo; hydroxy; (C1-C5) alkyl; (C2-C5) alkenyl; (C1-C5) alkoxy; (C3-C6) cycloalkoxy; trifluoromethyl; nitro; xe2x80x94C(xe2x95x90O)OR9; xe2x80x94C(xe2x95x90O)NR9R10, xe2x80x94NR9R10, and xe2x80x94S(xe2x95x90C)2NR9R10;
where in preferred embodiments, said aryl moiety comprises a member selected from the group consisting essentially of phenyl; naphthyl; indenyl (from 2,3-dihydro-1H-indene); indanyl; and fluorenyl (from 9-H-fluorene);
where in more preferred embodiments said aryl moiety comprises a member independently selected from the group consisting essentially of phenyl and indanyl;
where in preferred embodiments, said heterocyclyl moiety comprises a member independently selected from the group consisting essentially of acridinyl; benzimidazolyl; benzodioxoiane; 1,3-benzodioxol-5-yl; benzo[b]furanyl; benzo[b]thiophenyl; benzoxazolyl; benzthiazolyl; carbazolyl; cinnolinyl; 2,3-dihydrobenzofuranyl; 1,3-dioxane; 1,3-dioxolane; 1,3-dithiane; 1,3-dithiolane; furanyl; imidazolidinyl; imidazolinyl; imidazolyl; 1H-indazolyl; indolinyl; indolyl; 3H-indolyl; isoindolyl; isoquinolinyl; isothiazolyl; isoxazolyl; morpholinyl; 1,8-naphthyridinyl; oxadiazolyl; 1,3-oxathiolane; oxazolidinyl; oxazolyl; oxiranyl; parathiazinyl; phenazinyl; phenothiazinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; pteridinyl; pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolo[1,5-c]triazinyl; pyrazolyl; pyridazinyl; pyridyl; pyrimidinyl; pyrimidyl; pyrrolyl; pyrrolidinyl; purinyl; quinazolinyl; quinolinyl; 4H-quinolizinyl; quinoxalinyl; tetrazolidinyl; tetrazolyl; thiadiazolyl; thiazolidinyl; thiazolyl; thienyl; thiomorpholinyl; triazinyl; and triazolyl; and
where in more preferred embodiments said heterocyclyl moiety comprises a member independently selected from the group consisting essentially of pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl;
R9 and R10 are independently hydrogen or (C1-C4) alkyl substituted by 0 to 3 fluorine atoms;
RB1 is a member independently selected from the group consisting essentially of hydrogen; (C1-C9) alkyl; (C2-C3) alkenyl; phenyl; (C3-C7) cycloalkyl; and xe2x80x94(C1-C2) alkyl(C3-C7) cycloalkyl; wherein said alkyl, alkenyl and phenyl RB1 groups are substituted with 0 to 3 substituents independently selected from the group consisting essentially of methyl;ethyl; trifluoromethyl; and halo; and
R1a and R1b are each individually and independently a member selected from the group consisting essentially of hydrogen and the substituents defined by partial Formulas (5.12); (5.14); (5.16); (5.18); (5.21); (5.23); (5.25); (5.26); and (5.28) below, provided that both of R1a and R1b cannot be hydrogen at the same time;
wherein preferred embodiments comprise compounds where one of R1a and R1b is independently selected as hydrogen;
wherein said substituents in addition to hydrogen which define each of R1a and R1b comprise a member independently selected from the group consisting essentially of the moieties of partial Formulas (5.12); (5.14); (5.16); (5.18); (5.21); (5.23); (5.25); (5.26); and (5.28):
(I-A) 
wherein R2, R3, and R4 are independently selected from the group consisting essentially of hydrogen and (C1-C4) alkyl substituted by 0 to 3 substituents R5, where the substituent R5 is selected from the group consisting essentially of fluorine, chlorine, methyl, trifluoromethyl hydroxy, and methoxy;
where a preferred embodiment comprises a compound wherein R2, R3, and R4 are methyl and there are 0 substituents R5, represented by Formula (5.13): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof;
(I-B) R1a is R6 and R1b is the group. 
wherein R6 is a member independently selected from the group consisting essentially of (C1-C4)alkyl; (C1-C4)alkoxy; and hydroxy;
where a preferred embodiment comprises a compound where R6 is ethoxy, represented by Formula (5.15): 
and pharnaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechoL compounds, e.g., trepibutone, of Formula (5.14) are disclosed in Murata et al. U.S. Pat. No. 3,943,169, which is incorporated herein by reference in its entirety;
(I-C) 
wherein R8, R9 and R10 are independently selected from the group consisting essentially of hydrogen and (C1-C4) alkyl substituted by 0 to 3 substituents is a member independently selected R5, where the substituent R5 is as defined herein;
where a preferred embodiment comprises a compound where R8 and R9 are methyl and R10 is methoxy, represented by Formula (5.17): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., mebeverine, of Formula (5.16) are disclosed in Kralt et al. U.S. Pat. No. 3,265,577, which is incorporated herein by reference in its entirety;
(I-D) R1a and R1b are taken together to form the moiety of partial Formula (5.18): 
wherein p is 0 or p is 1 and W is xe2x80x94CH2xe2x80x94 or xe2x80x94NHxe2x80x94; R12 is absent or is (C1-C4) alkyl; RA and RB are as defined herein; and R13 is xe2x80x94CH3 or is the remainder of the moiety of Formula (5.18) whereby a bis compound is formed as represented by Formula (5.19): 
wherein HX is an acid addtion salt,
where a preferred embodiment comprises a compound where RA and RB are cyclohexyl and ethyl, the acid addtion salt is besylate, and R12 is methyl, represented by Formula (5.19): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., atracurium besylate, of Formula (5.19) are disclosed in Hill et al. published International Application WO 92/00965, which is incorporated herein by reference in its entirety;
(I-E) 
wherein R14, R15, and R16 are each a member independently selected from the group consisting essentially of xe2x80x94NH2; xe2x80x94NH(C1-C4) alkyl; and xe2x80x94N[(C1-C4) alkyl]2, where the alkyl groups are selected independently of each other;
where a preferred embodiment comprises a compound where R14, R15, and R16 are each xe2x80x94NH2, represented by Formula (5.21): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., troxipide, of Formula (5.21) are disclosed in Irikura et al. U.S. Pat. No. 3,647,805, which is incorporated herein by reference in its entirety;
(I-F) 
where the moiety 
xe2x80x83presents the residue of a saturated secondary heterocyclic base having 4, 5, 6, or 7 atoms in the ring, where X is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94; and preferably said secondary heterocyclic base is a member selected from the group consisting essentially of pyrrolidine, 1,3-thiazolidine, imidazolidine, 1,2-oxazolidine, 1,3-oxazolidine, piperidine, piperazine, tetrahydro-1,2-oxazine, tetrahydro-1,3-oxazine, tetrahydro-1,4-oxazine, i.e., morpholine, tetrahydro-1,4-thiazine, and perhydroazepine;
where preferred embodiments of this type include compounds which may be represented by the following Formula (5.24):
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., trithiozine, of Formula (5.23) are disclosed in Pifferi U.S. Pat. No. 3,862,138, which is incorporated herein by reference in its entirety;
(I-G) 
wherein R14 is as defined herein; and R18 is (C1-C4) alkyl or (C2-C4) alkenyl where said alkyl and alkenyl groups are substituted by 0 to 3 substituents R5, where the substituent R5 is selected from the group consisting essentially of fluorine, chlorine, methyl, trifluoromethyl hydroxy, and methoxy;
where a preferred embodiment comprises a compound where R14 is xe2x80x94NH2, and R18 is prop-2-en-1-yl, represented by Formula (5.27): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof,
(I-H) R1a and R1b are taken together to form the moiety: 
wherein the dashed line represents an optional double bond; YA is xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94C(xe2x95x90O)NHxe2x80x94; or xe2x80x94C(xe2x95x90O)N(CH3); YB is a member selected from the group consisting essentially of a direct single bond; a direct double bond; xe2x80x94CH2xe2x80x94; xe2x80x94CH2CH2xe2x80x94; xe2x80x94CH2CH2CH2; xe2x95x90CHxe2x80x94; xe2x95x90CHCH2xe2x80x94; xe2x95x90CH CH2CH2CH2xe2x80x94; xe2x95x90CHCH2CH2CH2CH2xe2x80x94; and xe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94; and YC is a member selected from the group consisting essentially of cyclohexyl; phenyl substituted by 0 to 3 R20 where R20 is a member selected from the group consisting essentially of methyl, methoxy, hydroxy, benzyloxy, and nitro; pyridyl; 1-naphthyl; 2-naphthyl;
where a preferred embodiment comprises a compound where YA is xe2x80x94C(xe2x95x90O)xe2x80x94; YB is xe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94; and YC is phenyl; represented by Formula (5.29): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof, and
where further details concerning predecessor catechol compounds of Formula (5.28) are disclosed in Sugimoto et al. U.S. Pat. Nos. 4,895,841 and 5,100,901, which are incorporated herein by reference in their entireties.
(II) Bioisostere Replacement Compounds Active As Adrenergic xcex11-Antagonists and xcex21-Agonists
The gist of the present invention is the discovery that the indazole nucleus is a moiety which is capable of being a bioisostere replacement for the catechol moiety which is an essential part of numerous endogenous ligands acting on important adrenergic receptors and thereby carrying out essential metabolic functions in the body. The indazole nucleus is also a bioisostere replacement for the catechol moiety which is an essential part of numerous drugs which have been and in the future will be created and developed for therapeutic treatments as detailed further herein.
The present invention is especially concerned with the xcex11-antagonist and xcex21-agonist classes of adrenergic agents which have a catechol moiety as a central and characteristic portion of their overall chemical structure, for which bioisostere replacement with an indazole moiety may be carried out in accordance with the present invention, i.e., while retaining the type of biological activity exhibited by the original catechol-containing compound.
One important therapeutic class of catechol-containing xcex11-receptor antagonists is that used as antihypertensive agents. Examples of such agents include the following:
vesnarinone, which acts as a cardiostimulant and as a coronary vasodilator: 
trimazosin, terazosin, prazosin, doxazosin, alfuzosin, and bunazosin, which are antihypertensive agents: 
dilazep, which is a coronary vasodilator: 
cinepazide, which is a peripheral vasodilator: 
cinepazet, which is an antianginal agent: 
and butobendine, which is an antiarrhythmic agent which increases cardiac blood flow: 
Another important therapeutic class of catechol-containing xcex21-receptor agonists is that used as agents which favorably affect the contractions of heart muscle. Examples of such agents include ibopamine which is an inotropic agent with dopaminergic and adrenergic agonist activities useful as a cardiotonic: 
denopamine and dobutamine which are selective xcex21-adrenoceptor agonist with positive inotropic activity useful as a cardiotonics: 
and bevantolol which is a cardioselective xcex21-adrenergic blocker useful as an antianginal, antihypertensive and antiarrhythmic agent: 
Other types of catechol-containing adrenergic receptor agonists and antagonists are aiso suitable for indazole bioisostere replacement in accordance with the present invention. For example, dipivefrin is an adrenergic agent which is ophthalmically active and useful as an antiglaucoma agent: 
and bitolterol is a xcex22-adrenergic agonist useful as a bronchodilator: 
In the basic biosynthesis route for catecholamine production in the body of a mammal, the hydroxylation of tyrosine is regarded as the rate-limiting step. In turn, tyrosine hydroxylase is activated following stimulation of adrenergic nerves or the adrenal medulla. The enzyme is a substrate for cyclic AMP-dependent and Ca2+-calmodulain-sensitive protein kinase and protein kinase C. Kinase catalyzed phosphorylation may also be associated with increased hydroxylase activity. This constitutes a mechanism which acts acutely and permits the body to increase catecholamine biosynthesis responsive to nerve stimulation.
The classification and properties of the different types of adrenergic receptors has been described above briefly, but an understanding of these characteristics is essential to an appreciation of the remarkably diverse effects of the catecholamines and related sympathomimetic agents. In turn, this appreciation is imperative if one is to grasp the extensive scope and surprising level of biological activities resulting from the bioisosteric replacement of the catechol moiety in accordance with the present invention.
The responses which follow activation of all of the various types of adrenergic receptors are mediated by G protein effects on the generation of a series of second messengers and on the activity of ion channels. Thus, there are three types of protein interacting in this system, the adrenergic receptor, the G protein, and the effector enzyme, i.e., the ion channel. Although the adrenergic receptors are characterized by heterogeneity of action, they are a closely related family of proteins; and they are also closely related in terms of both structure and functionality to a wide variety of other hormones and neurotransmitters that are coupled to G proteins. Conserved membrane spanning regions of the adrenergic receptors create ligand-binding pockets that are crucially involved in binding.
For example, the individual amino acids of the xcex22-adrenergic receptor which interact with the functional groups of the catecholamine agonist molecule have been identified. Other residues within the transmembrane domains have been found to be particularly involved in antagonist interactions. All of the xcex2-adrenergic receptors stimulate adenylyl cyclase through interaction with Gs protein, which leads in turn to the accumulation of cyclic AMP, activation of the cyclic AMP-dependent protein kinase, and altered function of numerous cellular proteins as a result of their phosphorylation. Accordingly, it has become accepted in the art that there are multiple points of regulation of the responsiveness of the adrenergic receptors in addition to the receptors themselves, and that these include G proteins, adenylyl cyclase, and cyclic nucleotide phosphodiesterase.
Sympathomimetic drugs exhibit actions which elicit all of the above responses, although the level of response in each case may vary considerably. Many sympathomimetic drugs influence both xcex1-receptors and xcex2-receptors, but usually not equally. In fact, the ratio of such activities constitutes a broad spectrum with predominantly xcex1 activity at one end in the case of phenylephrine, to predominantly xcex2 activity at the other end in the case of isoproterenol. While xcex2-phenylethylamine is the simplest and therefore parent compound for the sympathomimetic amine drugs discussed herein, the particular class of sympathomimetic drugs with which the present invention is concerned are all ortho-dihydroxybenzenes, i.e., catecholamines.
Some key structure-activity relationships have been established heretofore for the sympathomimetic catecholamines. For example, when the aromatic ring and the amine group are separated by two carbon atoms, the level of sympathomimetic activity is at its highest. Increase in size of the alkyl substituents on the amine group increases xcex2-receptor activity. For example, the rather low level of xcex22 activity in norepinephrine is increased dramatically by the addition of a methyl group to form epinephrine. Selectivity for xcex22 over xcex21 receptors requires other substitutions. The presence of the ortho-dihydroxy substitutions at positions 3- and 4-, which makes these compounds catechols, is required for maximal xcex1 and xcex2 activity. Studies carried out heretofore on the xcex2-adrenergic receptor strongly suggest that this optimization of activity results from the formation of hydrogen bonds between the 3- and 4-hydroxy groups of the catechol and corresponding hydroxyl groups on serine residues 204 and 207 which lie in the fifth membrane-spanning region of the receptor protein. These studies also suggest that aspartate 113, which lies in the third membrane-spanning region of the xcex2-adrenergic receptor, interacts with the amine group of the catecholamine to form an electrostatic bond. It can also be inferred from these spatial relationships that the catecholamine in question binds parallel to the plane of the xcex2-adrenergic receptor membrane, forming a bridge between the two above-mentioned membrane spans.
Where the hydroxyl groups of the catecholamine are not in the ortho-position but in the meta-position, i.e., at positions 3- and 5-, xcex22-receptor selectivity is conferred on the compound, provided that it has a large amino substituent. Thus, metaproterenol, terbutaline and similar compounds are administered as therapeutic agents to asthma patients, where they relax the bronchial musculature while causing less direct cardiac stimulation than other less selective agents:* 
In compounds where the hydroxyl groups on the aromatic ring are absent, as well as the xcex2-hydroxyl group of the side chain, the activity of the compounds is limited almost exclusively to causing the release of norepinephrine from adrenergic nerve terminals.
The site of action of a compound, i.e., its tissue compartmentalization, is also important to its therapeutic utilization. For example, the dihydroxy substitution of the catechols makes them less lipophilic, and thus unsubstituted or alkyl-substituted compounds are more able to cross the blood-brain barrier and be active in the central nervous system rather than the sympathetic nervous system. Accordingly, ephedrine, amphetamine, and methamphetamine posses considerable central nervous system activity, while on the other hand, compounds lacking the polar hydroxyl groups lose their direct sympathomimetic activity.
The rate of catabolism, i.e., the duration of action of the catecholamines is also important to their therapeutic use. For example, the catecholamines have a very short duration of action and are rapidly inactivated in the intestinal mucosa and liver by catechol-O-methyltransferase before reaching systemic circulation. They are thus ineffective when administered orally.
The structures of some of the above recited catechol-containing adrenergic agents which are suitable for indazole bioisostere replacement may be illustrated in their indazole form as follows: 
The subject matter of the present invention includes within its scope all and every indazole-for-catechol bioisostere replacement relating to xcex11-antagonist and xcex21-agonist classes of adrenergic agents, both as novel indazole compounds in particular and as said replacements in general. Also included within the scope of the present invention are the therapeutic methods of treatment and the pharmaceutical compositions relating thereto in which the active ingredient is an indazole-for-catechol bioisostere replacement compound, and in preferred embodiments of the present invention is as described in more detail further below.
Accordingly, the present invention relates in particular to indazole-for-catechol bioisostere replacements active as xcex11-antagonist and xcex21-agonist adrenergic agents, comprising a compound of Formulas (6.22) or (6.23):
(II) 
wherein
RC2 and RA2 and RB2 are defined the same as RC1 and RA1 and RB1 herein under Formulas (5.10) and (5.11), including preferred embodiments thereof, but are selected on an independent basis therefrom; and
R2a and R2b are each individually and independently a member selected from the group consisting essentially of hydrogen and the substituents defined by partial Formulas (6.24), (6.26), (6.41), (6.43), (6.48), and (6.50) below, provided that both of R2a and R2b cannot be hydrogen at the same time;
wherein preferred embodiments comprise compounds where one of R2a and R2b is independently selected as hydrogen;
wherein said substituents in addition to hydrogen which define each of R2a and R2b comprise a member independently selected from the group consisting essentially of the moieties of partial Formulas (6.24), (6.26), (6.41), (6.43), (6.48), and (6.50):
(II-A) 
wherein the dashed line represents an optional double bond; R23 is a member selected from the group consisting essentially of hydrogen; (C1-C4) alkyl, (C2-C4) alkenyl, and phenyl(C1-C4) alkyl-, where said alkyl,alkenyl, and phenyl or alkyl group attached thereto are substituted by 0 to 3 substituents R5, where the substituent R5 is as defined herein, but independently selected therefrom; and R24 is a member selected from the group consisting essentially of hydrogen and (C1-C4) alkoxy;
where a preferred embodiment comprises a compound where R23 and R24 are each hydrogen, e.g., a visnarinone bioisostere, represented by Formula (6.25): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., vesnarinone, of Formula (6.0) are disclosed in Tominaga et al. U.S. Pat. No. 4,415,572, which is incorporated herein by reference in its entirety;
(II-B) R2a and R2b are taken together to form the moiety of partial Formula (6.26): 
wherein E represents N, resulting in a pyrimidinyl moiety and overall a quinazoline series of compounds; or represents CH, resulting in a pyridyl moiety and overall a quinoline series of compounds; R25 and R26 are each a member independently selected from the group consisting essentially of hydrogen; (C1-C6)alkyl; (C2-C6)alkenyl; (C3-C8)cycloalkyl; hydroxy(C1-C6)alkyl; phenyl; benzyl; phenylethyl; and 2-furfuryl; and
R27 is independently selected from the group consisting essentially of:
(a) acetylamino of partial Formula (6.27): 
xe2x80x83wherein R28 is a member selected from the group consisting essentially of hydrogen; acetyl; (C1-C6) alkyl; and (C2-C6) alkenyl;
(b) amino or substituted amino of partial Formula (6.28): 
xe2x80x83wherein R25 and R26 are as defined further above;
(c) morpholino; 1-azacycloheptyl; 1-azacyclooctyl; pyrrolidino; or piperidino;
(d) N-substituted piperazino of partial Formula (6.29): 
xe2x80x83wherein R29 is a member selected from the group consisting essentially of hydrogen; (C1-C6) alkyl; hydroxy(C1-C6) alkyl; allyl; propargyl; 2-methylallyl; phenyl optionally substituted by bromo or chloro; benzyl optionally substituted by bromo or chloro; trifluoromethyl; methoxyphenyl; methylphenyl; carboxylic acid (C1-C6) alkyl ester; carboxylic acid (C2-C6) alkenyl ester; and xe2x80x94C(xe2x95x90O)xe2x80x94R30, where R30 is a member independently selected from the group consisting essentially of (C1-C6) alkyl; xe2x80x94Oxe2x80x94(C1-C6) alkyl; hydroxy(C1-C6) alkylxe2x80x94Oxe2x80x94; xe2x80x94(C2-C6) alkenyl; phenyl optionally substituted by bromo, chloro, methyl, 3,4,5-trimethoxy, or trifluoromethyl; naphthyl; furyl; benzofuryl; thienyl; pyridyl; tetrahydrofuryl; and tetrahydropyran;
(e) piperidino of partial Formula (6.30): 
xe2x80x83wherein R31 is a member independently selected from the group consisting essentially of hydrogen; (C1-C6) alkyl; (C1-C4) alkoxy; hydroxy; hydroxy(C1-C3) alkyl; phenyl; benzyl; and 4-phenyl-4carboxylic acid (C1-C6) alkyl ester;
(f) 4-(1,4-benzodioxan-2-carbonyl)-piperazin-1-yl of partial Formula (6.31): 
xe2x80x83wherein R33 and R34 are each independently a member selected from the group consisting essentially of hydrogen; (C1-C6) alkyl; (C1-C6) alkoxy; bromo, chloro and fluoro; xe2x80x94C(xe2x95x90O)(C1-C6)alkyl; xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6) alkyl; xe2x80x94C(xe2x95x90O)NR36R37 and xe2x80x94S(xe2x95x90O)2 NR36R37, where R36 and R37 are each independently hydrogen or (C1-C6)alkyl; R35 is independently hydrogen or (C1-C6)alkyl; and X is xe2x80x94CHR35xe2x80x94 or xe2x80x94CH2CH2xe2x80x94, where R35 is as defined above, selected on an independent basis;
(g) moiety of partial Formula (6.32): 
wherein L is absent or represents (i) a heterocyclic group of partial Formula (6.32.1): 
where N is attached to the 2-position of the guinoline or quinazoline ring; Aa is absent or represents C(xe2x95x90O) or S(xe2x95x90O)2; Za represents CH or N; m is an interger selected from 1 and 2, as well as from 0 when Za represents CH; and n is an integer selected from 1, 2, and 3; provided that the sum of m and n is an integer selected from 2, 3, 4, and 5; or (ii) a claim of partial Formula (6.32.2): 
where N is attached to the 2-position of the quinoline or quinozline ring; Ab and Zb have the same definition as Aa and Za above; Rt and Ru are each a member independently selected from the group consisting essentially of hydrogen and (C1-C4)alkyl; and p is an integer selected from 1, 2, and 3, provided that when Zb is CH, p may also be selected from 0; and R39 is a member independently selected from the group consisting essentially of 4-, 5-, and 6-membered heterocyclic rings containing 1 or 2 heteroatoms selected from N, O, and S, said ring optionally being fused to a benzene ring or to a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, said ring system comprising R39 being substituted by 0 to 2 members selected from the group consisting essentially of OH; (C1-C4)alkyl; (C1-C4)alkoxy; Br, Cl, or F; S(xe2x95x90O)2NRtRu; and NHS(xe2x95x90O)2(C1-C4)alkyl; and when said ring heteratom is S, it may be substituted by 0 to 2 oxygen atoms; and Rt and Ru are as defined above, but independently selected therefrom; (C1-C6)alkyl; benzyl optionally substituted by fluroro, bromo, chloro, or methoxy; and where Aa is absent, xe2x80x94C(xe2x95x90O)xe2x80x94R40, where R40 is a member independently selected from the group consisting essentially of (C1-C6)alkyl; phenyl optionally substituted by fluoro, bromo, chloro, methoxy, or methanesulfonyl; styryl optionally ring substituted by fluroro, bromo, chloro, methoxy, or 3,4-methylenedioxy; 4-morpholino; and 2-furyl; including particularly wherein R27 is a 1,4-diazepan of partial Formula (6.32.3): 
where Ra39 has the same definition as R39 but is independently selected therefrom; provided that xe2x80x94Lxe2x80x94R39 of partial Formula (6.32) may not be piperidine or piperazine;
(h) alkylenediamine of partial Formula (6.33): 
wherein R43 and R44 are each a member independently selected from the group consisting essentially of hydrogen; (C1-C4) alkyl; and benzyl; n is an integer selected from 2, 3, and 4; and R45 is (C3-C6) cycloalkyl or a radical selected from the group consisting of: 
in which m is an integer independently selected from 0, 1 and 2; and p is an integer independently selected from 0, 1 and 2;
where a preferred embodiment comprises a compound where R25 and R26 are both hydrogen; and R27 is (d)-partial Formula (6.29) where R29 is xe2x80x94C(xe2x95x90O)xe2x80x94R30 and R30 is hydroxy(C1-C6) alkyl-Oxe2x80x94, e.g., a trimazosin bioisostere, represented by Formula (6.34): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., trimazosin, of Formula (6.1) are disclosed in Hess U.S. Pat. No. 3,669,968, which is incorporated herein by reference in its entirety;
where further preferred embodiments comprise a compound where R25 and R26 are both hydrogen; and R27 is (d)-partial Formula (6.29) where R29 is xe2x80x94C(xe2x95x90O)xe2x80x94R30 and R30 is tetrahydrofuryl, e.g., a terazosin bioisostere, or tetrahydropyran, represented by Formulas (6.35) and (6.36), respectively: 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., terazosin, of Formula (6.2) are disclosed in Roteman U.S. Pat. No. 4,251,532, and where further details concerning predecessor catechol compounds of Formula (6.36) are disclosed in Winn et al. U.S. Pat. No. 4,026,894, both of which are incorporated herein by reference in their entireties;
where a still further preferred embodiment comprises a compound where R25 and R26 are both hydrogen; and R27 is (d)-partial Formula (6.29) where R29 is xe2x80x94C(xe2x95x90O)xe2x80x94R30 and R30 is furoyl, e.g., a prazosin bioisostere, represented by Formula (6.37): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof, and
where further details concerning predecessor catechol compounds, e.g., prazosin, of Formula (6.3) are disclosed in Hess U.S. Pat. No. 3,511,836, which is incorporated herein by reference in its entirety;
where a yet still further preferred embodiment comprises a compound where R25 and R26 are both hydrogen; and R27 is (f)-partial Formula (6.31) where R33, R34, and R35 are each hydrogen and X is xe2x80x94CH2xe2x80x94, e.g., a doxazosin bioisostere, represented by Formula (6.38): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., doxazosin, of Formula (6.4) are disclosed in Campbell U.S. Pat. No. 4,188,390, which is incorporated herein by reference in its entirety;
where an additional preferred embodiment comprises a compound where R25 and R26 are both hydrogen; and R27 is (g)-partial Formula (6.32) where L is absent; n is 2 and m is 3; Za is N; Aa is absent; R39 is xe2x80x94C(xe2x95x90O)xe2x80x94R40 and R40 is (C1-C6)alkyl; a bunazosin bioisostere, represented by Formula (6.39): 
or R40 is 4-morpholino, resulting in a bioisostere represented by Formula (6.39.1): 
or a bioisostoere represented by Formula (6.39.2): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., bunazosin, of Formula (6.6) are disclosed in Takahashi and Sugimoto U.S. Pat. No. 3,920,636, which is incorporated herein by reference in its entirety; and
where an another preferred embodiment comprises a compound where R25 and R26 are both hydrogen; and R27 is (h)-partial Formula (6.33) where n is 3; R43 is methyl, R44 is hydrogen, and R45 is a radical: 
where m is 1, which is an alfuzosin bioisostere, represented by Formula (6.40): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., alfuzosin, of Formula (6.5) are disclosed in Manoury U.S. Pat. No. 4,315,007 which is incorporated herein by reference in its entirety;
(II-C) 
wherein m is an integer independently selected from 2 and 3 in each instance of its occurrence; n is an integer selected from 2, 3, and 4; p is an integer selected from 2 and 3; and n and p together represent a total which is an integer selected from 5, 6, and 7;
where a preferred embodiment comprises a compound where RC2 is methoxy; where m in both instances is 3; n is 2; and p is 3, e.g., a dilazep bioisostere, represented by Formula (6.42): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., dilazep, of Formula (6.7) are disclosed in Arnold et al. U.S. Pat. No. 3,532,685, which is incorporated herein by reference in its entirety;
(II-D) 
wherein R47 is a member independently selected from the group consisting essentially of:
(a) (C1-C4) alkyl optionally substituted by 1 or 2 hydroxyl groups; phenyl(C1-C4) alkyl- optionally substituted on the phenyl portion thereof by 1 or 2 hydroxyl groups; and cinnamyl;
(b) xe2x80x94CH2C(xe2x95x90O)NHR48 where R48 is a member independently selected from the group consisting essentially of (C1-C4) alkyl; and phenyl optionally substituted by (C1-C4) alkoxy, trifluoromethyl, fluoro, bromo, or chloro;
(c) xe2x80x94CH2C(xe2x95x90O)NHR49R50 where R49 and R50 are each defined the same as R48; but are selected on an independent basis therefrom;
(d) a radical of partial Formula (6.44): 
xe2x80x83wherein the nitrogen atom forms part of a heterocyclic radical selected from the group consisting essentially of morpholino; hexamethylene-imino; and pyrrolidino; and
(e) xe2x80x94CH2C(xe2x95x90O)OR51 where R51 is hydrogen or (C1-C4) alkyl;
where a preferred embodiment comprises a compound where RC2 is methoxy, giving the exclusionary form of the bioisostere; and where R47 is a radical of partial Formula (6.44) in which the nitrogen atom forms the heterocyclic radical pyrrolidino; resulting in cinepazide exclusionary bioisostere, represented by Formula (6.45): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., cinepazide, of Formula (6.8) are disclosed in Fauran et al. U.S. Pat. No. 3,634,411, which is incorporated herein by reference in its entirety; and
where another preferred embodiment comprises a compound where RC2 is hydrogen, giving the inclusionary form of the bioisostere, or is methoxy, giving the exclusionary form of the bioisostere; and where R47 is a radical of partial formula (e) in which R51 is ethyl; resulting in cinepazet inclusionary and exclusionary bioisosteres, represented by Formula (6.46) and (6.47), respectively: 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., cinepazet, of Formula (6.9) are disclosed in Fauran et al. U.S. Pat. No. 3,590,034, which is incorporated herein by reference in its entirety;
(II-E) 
wherein RC2 is a member independently selected from the group consisting essentially of hydrogen; hydroxy; and xe2x80x94Oxe2x80x94(C1-C4) alkyl, in accordance with whether an inclusionary or exclusionary bioisostere is intended; and R54a and R54b are independently selected from the group consisting essentially of CnH2n+1 where n is an integer selected from 1, 2, 3, and 4;
where a preferred embodiment comprises a compound where RC2 is methoxy, giving the exclusionary form of the bioisostere; and where n=1 so that both R54a and R54b are methyl; resulting in butobendine exclusionary bioisostere; represented by Formula (6.49): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., butobendine, of Formula (6.10) are disclosed in Eckstein et al. U.S. Pat. No. 4,021,473, which is incorporated herein by reference in its entirety;
(II-F) 
wherein
R57 is a member independently selected from the group consisting essentially of hydrogen; (C1-C2) alkyl; and hydroxy;
R58 is a member independently selected from the group consisting essentially of hydrogen; and (C1-C2) alkyl;
W is xe2x80x94C(R64)(R65)xe2x80x94; xe2x80x94CH(R64)CH(R65)xe2x80x94; or xe2x80x94CH(R64)CH(R65)CH2xe2x80x94; where R64 is a member independently selected from the group consisting essentially of hydrogen and methyl; and R65 is a member independently selected from the group consisting essentially of hydrogen, methyl, and hydroxy;
R59 is a member selected independently from the group consisting essentially of hydrogen; methyl; phenyl; and benzoyl; where said phenyl and benzoyl groups are optionally substituted by a member independently selected from the group consisting essentially of m-hydroxy; p-hydroxy; m- and p-dihydroxy; m-(C1-C2) alkyl; (C1-C3) alkoxy; fluoro; chloro; cyano; hydroxymethyl; acetyl; and o-allyl; and
R60 is a member independently selected from the group consisting essentially of hydrogen; and methyl;
where a preferred embodiment comprises a compound where R57, R58, and R60 are each hydrogen; W is xe2x80x94C(R64)(R65)xe2x80x94 where R64 and R65 are both hydrogen; and R59 is hydrogen; resulting in an ibopamine bioisostere, represented by Formula (6.51): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., ibopamine, of Formula (6.11) are disclosed in Casagrande and Ferrari U.S. Pat. No. 4,218,470, which is incorporated herein by reference in its entirety;
where another preferred embodiment comprises a compound where R57, R58, and R60 are each hydrogen; W is xe2x80x94CH(R64)CH(R65)xe2x80x94 where R64 is hydrogen and R65 is hydroxy; and R59 is phenyl substituted by m-hydroxy or p-hydroxy; resulting in a denopamine bioisostere, represented by Formula (6.52): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., denopamine, of Formula (6.12) are disclosed in lkezaki et al. U.S. Pat. No. 4,032,575, which is incorporated herein by reference in its entirety;
where yet another preferred embodiment comprises a compound where R57, R58, and R60 are each hydrogen; W is xe2x80x94CH(R64)CH(R65)CH2xe2x80x94 where R64 is methyl and R65 is hydrogen; and R59 is phenyl substituted by p-hydroxy; resulting in a dobutamine bioisostere, represented by Formula (6.53): 
xe2x80x83and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., dobutamine, of Formula (6.13) are disclosed in Tuttle and Mills U.S. Pat. No. 3,987,200, which is incorporated herein by reference in its entirety;
where a still further preferred embodiment comprises a compound where R57, R58, and R60 are each hydrogen; W is xe2x80x94CH(R64)CH(R65)CH2xe2x80x94 where R64 is hydrogen and R65 is hydroxy; and R59 is benzoyl m-methyl; resulting in a bevantolol bioisostere, represented by Formula (6.54): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof, and
where further details concerning predecessor catechol compounds, e.g., bevantolol, of Formula (6.14) are disclosed in Holmes and Meyer U.S. Pat. No. 3,857,891, which is incorporated herein by reference in its entirety;
where a yet still further preferred embodiment comprises a compound where R57 is hydroxy; R58 and R60 are each hydrogen; W is xe2x80x94C(R64)(R65)xe2x80x94 where R64 and R65 are both hydrogen; and R59 is hydrogen; resulting in a dipivefrin bioisostere, represented by Formula (6.55): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., dipivefrin, of Formula (6.15) are disclosed in Hussain and Truelove U.S. Pat. No. 3,809,714, which is incorporated herein by reference in its entirety;
where a yet again still further preferred embodiment comprises a compound where R57 is hydroxy; R58 and R60 are each hydrogen; W is xe2x80x94C(R64)(R65)xe2x80x94 where R64 and R65 are both methyl; and R59 is methyl; resulting in a bitolterol bioisostere, represented by Formula (6.56): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., bitolterol, of Formula (6.16) are disclosed in Minatoya et al. U.S. Pat. No. 4,138,581, which is incorporated herein by reference in its entirety;
where a further preferred embodiment comprises a compound where R57 is hydroxy; R58 and R60 are each hydrogen; W is xe2x80x94C(R64)(R65)xe2x80x94 where R64 and R65 are both methyl; and R59 is hydrogen; resulting in a metaproterenol bioisostere, represented by Formula (6.57): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., metaproterenol, of Formula (6.17) are disclosed in Thoma and Zeile U.S. Pat. No. 3,341,594, which is incorporated herein by reference in its entirety;
where a further preferred embodiment comprises a compound where R57 is hydroxy; R58 and R60 are each hydrogen; W is xe2x80x94C(R64)(R65)xe2x80x94 where R64 and R65 are both methyl; and R59 is methyl; resulting in a terbutaline bioisostere, represented by Formula (6.58): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., metaproterenol, of Formula (6.18) are disclosed in Wetterlin and Svensson U.S. Pat. No. 3,937,838, which is incorporated herein by reference in its entirety.
(III) Bioisostere Replacement Compounds Active As Calcium Channel Antagonists
There is an important therapeutic class of calcium channel antagonists which includes verapamil, the members of which are characterized by having a catechol moiety as a central and characteristic portion of the overall chemical structure for which a biobioisostere replacement with an indazole moiety may be carried out in accordance with the present invention, i.e., while retaining the type of biological activity exhibited by the original catechol-containing compound. Calcium channel antagonists are useful in the treatment of variant agina, exertional angina, unstable angina, hypertension, myocardial ischemia, arrhythmia, and migraine prophylaxis. The catechol-containing chemical structure of verapamil may be illustrated by Formula (7.0): 
With regard to the catechol moieties of verapamil, it is essentially a dimer in structure, i.e., it comprises two identical, mer, units forming a dipolymer. It is noted that verapamil is not wholly symmetrical in structure, and this is not, totally, a dimer in form. Nevertheless, as already discussed further above, the dimeric nature of the catechol moieties affords two possibilities for different embodiments with respect to the indazole-for-catechol bioisostere replacements of the present invention. These are (1) that both sets of catechol moieties are replaced by indazoles, which is the preferred embodiment; and (2) that only one or the other catechol moiety is replaced by indazole, which is the less preferred embodiment.
Where the chemical structure which exits between the catechol moieities is not symmetrical, as is the case with verapamil, there arises the further posssilbity of two alternative embodiments where only one of the catechol moieties is being replaced by indazole. Accordingly, there are three indazole-for-catechol bioisostere replacement embodiments of verapamil for each isomeric form of the indazole in accordance with the present invention. All together, then, there are a total of six (6) bioisostere replacement embodiments of verapamil, which are represented by Formulas (7.1), (7.2), (7.3), (7.4), (7.5) and (7.6): 
Another calcium channel antagonist agent of the verapamil type is gallopamil, which may be represented by Formula (7.7): 
As already discussed in detail further above, the presence of a third, adjacent methoxy group on one of the phenyl groups of gallopamil affords the possibility of both inclusionary and exclusionary biobioisostere replacement embodiments in accordance with the present invention, which may be represented by Formulas (7.8) and (7.9): 
Further embodiments of gallopamil bloisostere replacements of the present invention are possible in view of the isomeric forms discussed further above regarding verapamil. Thus, gallopamil is a dimer in form, but is asymmetrical in structure, as was the case with verapamil. Further, there are two isomeric forms of the indazole replacement. All of these isomeric structures are present in each of the inclusionary and exclusionary embodiments of the indazole-for-catechol bioisostere replacements for gallopamil. Accordingly, there are a total of twelve (12) bioisostere replacement embodiments of gallopamil in accordance with the present invention.
Other verapamil type calcium channel antagonists which are suitable for making indazole-for-catechol replacement bioisosteres in accordance with the present invention comprise fantofarone and closely related aminoalkoxyphenyl derivatives. The indazole bioisosteres of these compounds, as do the indazole bioisosteres of the other verapamil type calcium channel antagonists described herein, possess calcium transport inhibitory properties, as well as bradycardic, hypotensive and antiadrenergic properties. The resulting indazole replacement bioisosteres are, accordingly, useful in the treatment of angina pectoris, hypertension, arrhythmia and cerebral circulatory insufficiency. They are also useful in the antitumor field, where they are potentiators of anticancer chemotherapeutic agents. Fantofarone and its indazole-for-catechol bioisostere replacement may be represented by Formulas (7.10) and (7.11), respectively: 
A further verapamil type of calcium channel antagonist which is suitable for making indazole-for-catechol replacement bioisosteres in accordance with the present invention is trimetazidine and closely related methoxy-benzyl-piperazines. Trimetazidine has a 2,3,4-trimethoxyphenyl structure, and therefore falls within the category of indazole-for-catechol bioisostere replacement embodiments of the present invention which may be inclusionary or exclusionary, as described in detail further above. This may be illustrated in the case of trimetazidine by Formulas (7.12), (7.13), and (7.14): 
The indazole-for-catechol bioisostere replacement embodiments of this type possess valuable pharmacological properties as peripheral vasodilators, an action which is exerted both on the peripheral circulation and on the coronary arteries. The mechanism of action involves the smooth muscle fibers of the vessel walls of the circulatory system, and does not involve the autonomous nervous system. Thus, the bioisosteres of the present invention may be used in the treatment of various circulatory disorders such as arteritis or coronary insufficiency.
Further verapamil type calcium channel antagonists which are suitable for making indazole-for-catechol replacement bioisosteres in accordance with the present invention comprise lomerizine and closely related 1-(2,3,4-trimethoxybenzyl-4-[bis(4-fluorophenyl)methyl]piperazine derivatives. The indazole bioisosteres of these compounds are useful as agents for improving cerebrovascular diseases of humans, and in particular are antimigraine agents. Lomerizine and its indazole-for-catechol bioisostere replacements, both inclusionary and exclusionary forms thereof as described above, may be represented by Formulas (7.15), (7.16) and (7.17): 
Cerebrovascular diseases include intracranial hemorrhages such as intracerebral hemorrhage or subarachnoid hemorrhage, as well as cerebral infarctions such as cerebral thrombosis or cerebral embolus, transient ischemic attack, and hypertensive encephalopathy. A key mechanism in these diseases is infaction of brain parenchymal tissue resulting directly from hemorrhage, thrombus, or an embolus within the brain, which leads in turn to glucose and oxygen insufficiency, depriving the neurons of needed sources of energy. Functional and organic disturbances result in the ischemic area; consequently, therapeutic agents which supply or enhance the supply of glucose and oxygen to the ischemic area by increasing cerebral blood flow are effective for the treatment and prevention of such cerebrovascular diseases.
Heretofore, therapeutic agents which have been used clinically for the purpose of treating said cerebrovascular diseases and their subsequent complications, and to prevent relapse, have included such compounds as cinnarizine, bencyclane fumarate, cyclandelate, and cinepazide maleate.
Still further verapamil type calcium channel antagonists which are suitable for making indazole-for-catechol replacement bioisosteres in accordance with the present invention comprise zatebradine and closely related 7,8-dimethoxy-3-benzazepin-2-one derivatives. The indazole bioisosteres of these compounds have long-lasting bradycardiac activity and reduce the oxygen requirements of the heart, with only slight side effects such as antimuscarinic activity. Zatebradine has an asymmetrical dimer structure, as discussed further above, and consequently affords a number of embodiments of the indazole-for-catechol bioisostere replacement compounds of the present invention. These are illustrated in Formulas (7.18), (7.19), (7.20), and (7.21): 
Accordingly, the present invention relates in particular to indazole-for-catechol bioisostere replacements active as calcium channel antagonists, comprising a compound of Formulas (7.22) or (7.23): 
wherein
RC3 and RA3 and RB3 are defined the same as RC1 and RA1 and RB1 herein under Formulas (5.10) and (5.11), including preferred embodiments thereof, but are selected on an independent basis therefrom; and
R3a and R3b are each individually and independently a member selected from the group consisting essentially of hydrogen and the substituents defined by partial Formulas (7.25); (7.28); (7.35); and (7.41) below, provided that both of R3a and R3b cannot be hydrogen at the same time;
wherein preferred embodiments comprise compounds where one of R3a and R3b is independently selected as hydrogen;
wherein said substituents in addition to hydrogen which define each of R3a and R3b comprise a member independently selected from the group consisting essentially of the moieties of partial Formulas (7.25); (7.28); (7.35); and (7.41):
(II-A) 
wherein R70 is a member independently selected from the group consisting essentially of hydrogen; (C1-C4) alkyl; phenyl; benzyl; and cyclohexyl; R71 is a member independently selected from the group consisting essentially of (C1-C4) alkyl; n is an integer independently selected from 2, 3, and 4; and m is an integer independently selected from 1, 2, and 3;
where preferred embodiments comprise compounds where R70 is isopropyl; R71 is methyl; n is 2; and m is 2, e.g., a verapamil bioisostere, represented by Formula (7.26): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., verapamil, of Formula (7.0) are disclosed in Dengel U.S. Pat. No. 3,261,859, which is incorporated herein by reference in its entirety;
where further preferred embodiments comprise compounds where RC3 is methoxy in Formulas (7.22) and (7.23) but is hydrogen in Formulas (7.24) and (7.25); R70 is isopropyl; R71 is methyl; n is 2; and m is 2, e.g., a gallopamil bioisostere based on the second indazole isomer as discussed further above, represented by Formula (7.27): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., gallopamil, of Formula (7.7) are also disclosed in said Dengel U.S. Pat. No. 3,261,859, which is incorporated herein by reference in its entirety;
(III-B) 
wherein R73 is a member independently selected from the group consisting essentially of hydrogen and (C1-C4) alkyl; R74 is a member independently selected from the group consisting essentially of a single bond and a linear- or branched-alkylene radical (C1-C5) alkyl; W1 is a member independently selected from the group consisting essentially of straight- and branched-alkylene radicals (C2-C5) alkyl, and 2-hydroxypropylene; R75 and R76 are members independently selected from the group consisting essentially of hydrogen, methyl, ethyl, chloro, and bromo; W2 is a member independently selected from the group consisting essentially of xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, and xe2x80x94SO2xe2x80x94; and A is a member indpendently selected from the group consisting essentially of
(a) 
wherein R77 and R78 are taken together with the carbon atom to which they are attached to form an optionally aromatic mono- or di-cyclic carbocyclic group having from 5 to 10 carbon atoms and optionally substituted in the xcex1-position with respect to the methylene group of partial Formula (7.29) by R84 as defined below ; an optionally aromatic 5-membered heterocyclic group where the heteroatoms or heterogroups are members independently selected from the group consisting essentially of O, S, N, xe2x80x94N(R79)xe2x80x94, O together with N, O together with xe2x80x94N(R79)xe2x80x94, S together with N, S together with xe2x80x94N(R79)xe2x80x94, N together with N, and N together with xe2x80x94N(R79)xe2x80x94, optionally substituted in the xcex1-position with respect to the methylene group of partial Formula (7.29) by R84 as defined below, where R79 is hydrogen, (C1-C4) alkyl, or phenyl; or an optionally aromatic 6- to 10-membered mono- or di-cyclic heterocyclic group, where the heteroatoms or heterogroups are members independently selected from the group consisting essentially of O, S, N, xe2x80x94N(R79)xe2x80x94, O together with N, O together with xe2x80x94N(R79)xe2x80x94, S together with N, S together with xe2x80x94N(R79)xe2x80x94, N together with N, and N together with xe2x80x94N(R79)xe2x80x94, optionally substituted in the xcex1-position with respect to the methylene group of partial Formula (7.29) by R84 as defined below, where R79 is hydrogen, (C1-C4) alkyl, or phenyl; 
xe2x80x83wherein
R80 and R81 are members independently selected from the group consisting essentially of hydrogen; (C1-C4) alkyl; phenyl; and taken together with the carbon atom to which they are attached represent an optionally aromatic 6-membered carbocyclic ring; R82 is O or S; R83 is O; S; or xe2x80x94N(R79)xe2x80x94; R84 is a member independently selected from the group consisting essentially of hydrogen; (C1-C4) alkyl; (C3-C7) cycloalkyl; benzyl; and phenyl optionally substituted with 1 to 3 substituents selected from the group consisting essentially of fluoro, chloro, bromo, (C1-C4) alkyl, (C1-C4) alkoxy, and nitro; and R85 and R86 are members independently selected from the group consisting essentially of hydrogen; (C1-C4) alkyl; and benzoyl;
where in preferred embodiments, the group A is a member independently selected from the group consisting essentially of phenyl, cyclohexenyl, indenyl, naphthyl, dihydronaphthyl, pyridyl, dihydropyridyl, furyl, dihydrofuryl, thienyl, dihydrothienyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isxoazolyl, thiazolyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl, quinolinyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, indolizinyl, thienopyridyl, tetrahydrothienopyridyl, pyrrolopyridyl, pyrazolopyridyl, pyrrolopyridazinyl, imidazopyridyl, dihydrofuranonyl, imidazolinonyl, and chromonyl;
where preferred embodiments comprise compounds where R73 is CH3xe2x80x94; R74 is xe2x80x94CH2CH2xe2x80x94; W1 is xe2x80x94CH2CH2xe2x80x94; R75 and R76 are both hydrogen; W2 is xe2x80x94SO2xe2x80x94; and A is a group of partial Formula (7.29) where R77 and R78 together are a di-cyclic heterocyclic group, where the heteroatom is N, substituted in the xcex1-position with respect to the methylene group of partial Formula (7.29) by R84, where R84 is isopropyl, resulting in a fantofarone bioisostere based on the second isomer of indazole as discussed further above, represented by Formula (7.34): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., fantofarone, of Formula (7.10) are disclosed in Gubin et al. U.S. Pat. No. 4,957,925, which is incorporated herein by reference in its entirety;
(III-C) 
wherein R88 is hydrogen or a group of partial Formula (7.36): 
where R89 is hydrogen or fluorine;
where preferred embodiments comprise compounds where R88 is partial Formula (7.36) where R89 is fluorine, a lomerizine bioisostere based on the second isomer of indazole, represented by Formulas (7.37) and (7.38): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., lomerizine, of Formula (7.15) are disclosed in Ohtaka et al. U.S. Pat. No. 4,663,325, which is incorporated herein by reference in its entirety;
where further preferred embodiments comprise compounds where R88 is hydrogen, a trimetazidine bioisostere based on the second isomer of indazole, represented by Formulas (7.39) and (7.40): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., trimetazidine, of Formula (7.12) are disclosed in Servier U.S. Pat. No. 3,262,852, which is incorporated herein by reference in its entirety;
(III-D) R3a and R3b are taken together to form the moiety of partial Formula (7.41): 
wherein A is xe2x80x94CH2CH2xe2x80x94; xe2x80x94CHxe2x95x90CHxe2x80x94; xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94; or xe2x80x94C(R94)xe2x95x90Nxe2x80x94 where R94 is (C1-C3) alkyl; and B is methylene; carbonyl; or thiocarbonyl; or A is xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94Nxe2x95x90CHxe2x80x94; xe2x80x94CH(OH)xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94; xe2x80x94C(xe2x95x90NOH)xe2x80x94C(xe2x95x90O)xe2x80x94; or xe2x80x94CH(NHR95)xe2x80x94C(xe2x95x90O)xe2x80x94, where R95 is hydrogen or (C1-C3) alkyl substituted by phenyl, methoxyphenyl, or dimethoxyphenyl; and B is methylene; E is a member independently selected from the group consisting essentially of n-(C2-C4) alkylene, optionally substituted by (C1-C3) alkyl, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene; G is a member independently selected from the group consisting essentially of n-(C1-C5) alkylene, optionally substituted by (C1-C3) alkyl, where one methylene group of an n-alkylene of 2 to 5 carbon atoms may be replaced by a carbonyl group, with the proviso that B represents a methylene or carbonyl group, or methylene-n-hydroxyalkylene of 1 to 4 carbon atoms, where the methylene group is attached to the nitrogen atom; R90 is a member independently selected from the group consisting essentially of hydrogen; (C1-C3) alkyl; phenyl(C1-C3) alkyl; (C1-C3) alkanoyl; (C1-C3) alkoxycarbonyl; and (C3-C5) alkenyl; and R91, R92, and R93 are each a member independently selected from the group consisting essentially of hydrogen; fluorine; chlorine; bromine; hydroxy; cyano; nitro; trifluoromethyl (C1-C4) alkyl; (C1-C4) alkoxy; (C1-C3) alkylamino; di(C1-C3) alkylamino; (C1-C3) alkanoylamino; (C1-C3) alkoxycarbonylamino; bis(C1-C3) alkoxycarbonylamino; (trifluoromethyl)methylamino; and (trifluoromethyl)ethylamino; and R91 and R92 taken together with each other are (C1-C2) alkylenedixoy;
where preferred embodiments comprise compounds where A is xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94; B is methylene; E is n-(C3) aikylene, i.e., n-propylene; R90 is methyl; G is n-(C2) alkylene, i.e. ethylene; and one of R91, R92, and R93 is hydrogen, while the other two are both (C1) alkoxy, i.e., methoxy; resulting in zatebradine bioisosteres based on the second isomer of indazole, represented by Formulas (7.42), (7.43), and (7.44): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., zatebradine, of Formula (7.18) are disclosed in Reiffen et al. U.S. Pat. No. 4,490,369, which is incorporated herein by reference in its entirety.
(IV) Bioisostere Replacement Compounds Active As Antineoplastic Agents
A known antineoplastic agent which has a catechol moiety as part of its essential structure is trimetrexate, which may be represented by Formula (8.3): 
Trimetrexate is an antifolate, i.e., an inhibitor of dihydrofolate reductase, related to methotrexate, which has provided consistent cure of choriocarcinoma. Trimetrexate is a lipid-soluble folate antagonist which facilitates penetration of the blood-brain barrier. Trimetrexate has also also been used successfully in the therapy of psoriasis, a non-neoplastic disease of the skin characterized by abnormally rapid proliferation of epidermal cells. Trimetrexate has also been beneficial in the treatment of Pneumocystis carinii. 
Another class of therapeutic agents useful in the treatment of neoplastic diseases is that of the protein tyrosine kinase inhibitors, which play a fundamental role in signal transduction pathways. Deregulated protein tyrosine kinase activity has been observed in many proliferative diseases such restenosis in addition to cancer and psoriasis. A number of tumor types have disfunctional growth factor receptor protein tyrosine kinases which result in inappropriate mitogenic signalling. Consequently, the therapeutic treatment of cancer has been based on agents which exhibit inhibition of protein tyrosine kinases, including particularly epidermal growth factor-receptor protein tyrosine kinase (EGF-R PTK). Among the most potent and selective inhibitors of epidermal growth factor-receptor protein tyrosine kinases are members of the class of 4-anilino-quinazolines. An example of such an inhibitor is the Parke-Davis compound PD-153,035, first described in Ward et al., Biochem. Pharmacol. (1994) 48(4) 659-666, and later by Fry et al., Science (1994) 265, 1093-1095, which may be represented by Formula (8.4): 
For acceptable levels of activity, e.g., selective blocking of EGF-R autophosphorylation or c-jun induction, the electron-withdrawing bromine group at the meta-position of the 4-anilino moiety is preferred, as is the presence of small electron-donating substituents at the 6- and 7-positions, e.g., the two methoxy groups which form a catechol moiety. Such compounds are suitable for indazole-for-catechol bioisostere replacement in accordance with the present invention, which may be represented by Formulas (8.5) and (8.6): 
The 4-position anilino moiety may also be replaced by other substituents which afford the same or enhanced levels of EGF-R PTK inhibition or improved selectivity with respect to other protein tyrosine kinases. The 4-position may be occupied by bicyclic aminoheteroaromatic moieties or by heterocyclyl-substituted-6,7-dimethoxy-quinazolines, e.g., the dihydro-indolyl compound CP-292,597, as represented in Formulas (8.7) and (8.8), respectively: 
The resulting compounds are suitable for indazole-for-catechol replacement in accordance with the present invention.
Further, suitable compounds result where the anilino nitrogen is methylated or replaced by oxygen or sulfur; a phenoxyanilino moiety is used; or the analogous phenethylamino moiety is present, as represented by the compounds of Formulas (8.9), (8.10), and (8.11), respectively: 
The resulting compounds are suitable for indazole-for-catechol replacement in accordance with the present invention.
Selective EGF-R PTK inhibitors have been obtained with quinazoline derivatives which have various substituents in the anilino side chains, e.g., an ethynyl moiety as in CP-358,774, or with 4-indolyl compounds, as represented by the compounds of Formulas (8.12) and (8.13), respectively: 
The resulting compounds are suitable for indazole-for-catechol replacement in accordance with the present invention.
The 4-position may be occupied by bicyclic aminoheteroaromatic moieties or by heterocyclyl-substituted-6,7-dimethoxy-quinazolines, e.g., the dihydro-indolyl compound CP-292,597. Modifications of the class of 4-anilino quinazolines described above have not been limited to the 4-anilino group alone. Basic amino side chains have been used in the 6-position of the quinazoline ring and various substituents have been added to the 4-anilino moiety in order to improve solubility of the 4-anilino-quinazolines, as illustrated by ZD-1839, a compound of Formula (8.18): 
The resulting compounds are suitable for indazole-for-catechol replacement in accordance with the present invention wherein the basic amino side chain at the 6-position of the predecessor compound is relocated to the corresponding position on the phenyl ring of the indazole group. This principle may be illustrated in the case of the ZD-1839 compounds by Formulas (8.19) and (8.20): 
Accordingly, the present invention relates in particular to indazole-for-catechol bioisostere replacements active as antineoplastic agents, especially inhibitors of protein tyrosine kinases, including particularly epidermal growth factor-receptor protein tyrosine kinase (EGF-R PTK), comprising a compound of Formulas (8.21) or (8.22):
(IV) 
wherein
RC4 and RA4 and RB4 are defined the same as RC1 and RA1 and RB1 herein under Formulas (5.10) and (5.11), including preferred embodiments thereof, but are selected on an independent basis therefrom; and
R4a and R4b are each individually and independently a member selected from the group consisting essentially of hydrogen and the substituents defined by partial Formulas (8.23); (8.28); (8.40); and (8.45) below, provided that both of R4a and R4b cannot be hydrogen at the same time;
wherein preferred embodiments comprise compounds where one of R4a and R4b is independently selected as hydrogen;
wherein said substituents in addition to hydrogen which define each of R4a and R4b comprise a member independently selected from the group consisting essentially of the moieties of partial Formulas (8.23); (8.28); (8.40); and (8.45):
(IV-A) 
wherein Z is 2-hydroxyethanesulfonic acid or glucuronic acid, as well as pharmaceutically acceptable prodrugs and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., trimetrexate, of Formula (8.3) are disclosed in Colbry U.S. Pat No. 4,376,858, which is incorporated herein by reference in its entirety;
where embodiments of the present invention comprising trimetrexate bioisosteres may be represented by Formulas (8.24), (8.25), (8.26) and (8.27): 
(IV-B) R4a and R4b are taken together to form the moiety of partial Formula (8.28): 
wherein Ar a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of from 5 to 12 atoms where each monocyclic ring may contain 0 to 3 heteroatoms, and each bicyclic ring may contain 0 to 4 heteroatoms selected from N, O, and S, provided said heteroatoms are not vicinal oxygen and/or sulfur atoms; W4 is a member independently selected from the group consisting essentially of a bond; xe2x80x94Oxe2x80x94; xe2x80x94Sxe2x80x94; xe2x80x94S(xe2x95x90O)xe2x80x94; xe2x80x94S(xe2x95x90O)2xe2x80x94; xe2x80x94OCH2xe2x80x94; xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94; xe2x80x94C(xe2x95x90S)xe2x80x94; xe2x80x94SCH2xe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94NHCH2xe2x80x94; xe2x80x94NHCH(R97)xe2x80x94, xe2x80x94N(R97)xe2x80x94 or xe2x80x94N(R97)CH2xe2x80x94 where R97 is (C1-C4) alkyl; xe2x80x94CH2xe2x80x94CH2xe2x80x94, and xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94; m is an integer selected from 0, 1, 2, and 3; and R96 is a member independently selected from the group consisting essentially of hydrogen; xe2x80x94(C1-C4) alkyl; xe2x80x94(C2-C4) alkenyl; -phenyl; phenyl(C1-C3) alkyl-; phenyl(C2-C3) alkenyl-; -hydroxy; hydroxy(C1-C4) alkyl-; xe2x80x94(C1-C4) alkoxy; (C1-C3) alkoxy(C1-C2) alkyl-; phenyl(C1-C3) alkoxy-; phenyloxy-; (C1-C4) alkylcarbonyloxy-; phenylcarbonyloxy-; bromo, chloro, or fluoro; (bromo, chloro, or fluoro)(C1-C3) alky-; -nitro; -cyano; -amino; mono- or di-(C1-C4) alkylamino-; (C1-C4) alkylcarbonylamino-; phenylcarbonylamino-; -carboxy; carboxy(C1-C3) alkyl-; (C1-C3) alkoxycarbonyl-; phenyl(C1-C3) alkoxycarbonyl; (C1-C3) alkoxycarbonyl(C1-C3) alkyl-; amino(C1-C3) alkoxy-; amido; mono- and di-(C1-C3) alkylamido; N,Nxe2x80x94(C1-C3) cycloalkylamido-; (C1-C3) alkylthio-; (C1-C3) alkylsulfinyl-; -sulfonyl; mono- and di-(C1-C3) alkylsulfonyl-; -sulfamoyl; mono- and di-(C1-C3) alkylsulfamoyl-; (bromo, chloro, or fluoro)phenyl-; benzoyl; and provided that m is 1, azido and R94a-ethynyl, where R94a is hydrogen or (C1-C6) alkyl substituted by 0 to 2 substituents where said substituent is a member independently selected from the group consisting essentially of hydrogen; amino; hydroxy; R94bxe2x80x94O; R94bxe2x80x94NH; and (R94b)2xe2x80x94N, where R94b is (C1-C4) alkyl,
where preferred embodiments comprise a compound wherein Ar as a monocyclic aryl or heteroaryl ring is a member independently selected from the group consisting essentially of substituted and unsubstituted benzene; pyrrole: thiophene; furan; thiazole; imidazole; pyrazole; 1,2,4-triazole; pyridine; 2(1H)-pyridone; 4(1H)-pyridone; pyrazine; pyrimidine; pyridazine; isothiazole; isoxazole; oxazole; and tetrazole; and wherein Ar as a bicyclic aryl or heteroaryl ring is a member independently selected from the group consisting essentially of substituted and unsubstituted naphthalene; tetralin; naphthyridine; benzofuran; benzothiophene; indole; 2,3-dihydroindole; 1H-indazole; indoline; benzopyrazole; 1,3-benzodioxole; benzoxazole; purine; coumarin; chromone; quinoline; tetrahydroquinoline; isoquinoline; benzimidazole; quinazoline; pyrido[2,3-b]pyrazine; pyrido[3,4-b]pyrazine; pyrido[3,2-c]pyridazine; pyrido[3,4-b]pyridine; 1H-pyrazole[3,4-d]pyrimidine; pteridine; 2(1H)-quinolone; 1(2H)-isoquinolone; 1,4-benzisoxazine; benzothiazole; quinoxaline; quinoline-N-oxide; isoquinoline-N-oxide; quinoxaline-N-oxide; quinazoline-N-oxide; benzoxazine; phthalazine; and cinnoline; and R96 is a member independently selected from the group consisting essentially of hydrogen; xe2x80x94(C1-C4) alkyl; xe2x80x94(C2-C4) alkenyl; hydroxy; xe2x80x94(C1-C4) alkoxy; bromo, chloro, or fluoro; (bromo, chloro, or fluoro)(C1-C3) alky-; -amino; mono- or di-(C1-C4) alkylamino-; (C1-C4) alkylcarbonylamino-; phenyicarbonylamino-; -carboxy; carboxy(C1-C3) alkyl-; amido; mono- and di-(C1-C3) alkylamido; N,Nxe2x80x94(C1-C3)cycloalkylamido-; (C1-C3) alkylthio-; (C1-C3) alkylsulfinyl-; mono- and di-(C1-C3) alkylsulfonyl-; mono- and di-(C1-C3) alkylsulfamoyl-;
where more preferred embodiments comprise a compound wherein Ar is substituted or unsubstituted benzene; pyridine; thiophene; naphthalene; quinoline; indole; 1H-pyrazole[3,4-d]pyrimidine; e.g., a bioisostere represented by Formulas (8.29) and (8.30): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., the compounds of Formula (8.9), are disclosed in Myers et al. International Pat. WO 95/15758, which is incorporated herein by reference in its entirety;
where further preferred embodiments comprise compounds wherein R4a and R4b are taken together to form the moiety of partial Formula (8.31): 
wherein R95 is a member independently selected from the group consisting essentially of hydrogen; hydroxy; bromo, chloro or fluoro; trifluoromethyl; amino; nitro; cyano; and (C1-C4) alkyl; and n is an integer selected from 1 and 2; and where especially preferred embodiments comprise a compound where R95 is bromo and is meta with respect to the 4-anilino moiety; and n is 1; e.g., a PD-153,035 bioisostere, represented by Formula (8.5) set out further above and repeated here: 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and
where further details concerning predecessor catechol compounds, e.g., PD-153,035, of Formula (8.4), are disclosed in Barker et al. European Pat. EP 566,226, which is incorporated herein by reference in its entirety;
where still further preferred embodiments comprise compounds wherein W4 is a bond; Ar is indole; and R96 is hydrogen; e.g., a bioisostere of the compounds of Formula (8.12), which may be represented by Formulas (8.32) and (8.33): 
xe2x80x83and pharmaceutically acceptable salts, prodrugs, and metabolites thereof;
where further details concerning predecessor catechol compounds, e.g., those of Formula (8.12), are disclosed in Myers et al. International Pat. WO 96/39145, which is incorporated herein by reference in its entirety;
where still yet further preferred embodiments comprise compounds wherein Ar is benzene; W4 is NH; and R96 is R94a-ethynyl, where R94a is hydrogen, e.g., bioisosteres of the compounds of Formula (8.13), which may be represented by Formulas (8.34) and (8.35): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof;
where further details concerning predecessor catechol compounds, e.g., compounds of Formula (8.13) are disclosed in Schnur and Arnold International Pat. WO 96/30347, which is incorporated herein in its entirety;
where additional preferred embodiments comprise compounds wherein Ar is indole; W4 is NH; and R96 is hydrogen, resulting in 4-(5-indolylamino)quinazoline compounds, e.g., bioisosteres of the compounds of Formula (8.7), which may be represented by Formulas (8.36) and (8.37): 
xe2x80x83and pharmaceutically acceptable salts, prodrugs, and metabolites thereof;
where further details concerning predecessor catechol compounds, e.g., compounds of Formula (8.7) are disclosed in Barker et al. European Pat. EP 602,851, which is incorporated herein in its entirety;
where further additional preferred embodiments comprise compounds wherein Ar is benzenee; W4 is xe2x80x94NHCH(R97)xe2x80x94 where R97 is (R)-methyl; and R96 is hydrogen, resulting in (R)-phenylethylamino compounds, e.g., bioisosteres of the compounds of Formula (8.11), which may be represented by Formulas (8.38) and (8.39): 
xe2x80x83and pharmaceutically acceptable salts, prodrugs, and metabolites thereof;
where further preferred embodiments comprise compounds wherein Ar is benzene; W4 is NH; m is 2; and R96 chloro or fluoro; e.g., bioisosteres of the compounds of ZD-1839 of Formula (8.18), which may be represented by Formulas (8.19) and (8.20) set out further above and repeated here: 
xe2x80x83and pharmaceutically acceptable salts, prodrugs, and metabolites thereof;
where further details concerning predecessor catechol compounds, e.g., compounds of ZD-1839 of Formula (8.18) are disclosed in Barker International Pat.""s WO 96/33977; WO 96/33978; WO 96/33979; WO 96/33980; and WO 96/33981; which are incorporated herein in their entireties;
(IV-C) 
wherein Z is a moiety of partial Formulas (8.41) and (8.42) 
wherein m is an integer selected from 0, 1, 2, 3, and 4; n is an integer selected from 0, 1, and 2; D is saturated carbon; oxy; or thio; R105 is a member independently selected, for each occurrence in partial Formulas (8.41) and (8.42), from the group consisting essentially of mono-, di-, or tri-fluoromethyl; bromo, chloro, or fluoro; nitro; hydroxy; amino; azido; isothiocyano; (C1-C4) alkyl; phenyl; thienyl; (C1-C4) alkoxy; benzyloxy; phenoxy; (C2-C6) alkenyl; (C2-C6) alkynyl; (C1-C4) alkylenedioxy; cyano; benzoylamino; trifluoromethylcarbonylamino; (C1-C4) alkanoylamino; (C1-C4) alkanoyl-N-mono- or xe2x80x94N,N-di-(C1-C4) alkylamino; (C1-C4) alkylsulfonylamino; trifluoromethylsulfonylamino; (C1-C4) alkylthio; (C1-C4) alkylsulfinyl; (C1-C4) alkylsulfonyl; pyrrol-1-yl; piperidin-1-yl; and pyrrolidin-1-yl; where said phenyl, benzyloxy, phenoxy and benzoylamino groups are optionally mono-substituted with a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; nitro; trifluoromethyl; hydoxy; and (C1-C4) alkyl; and where said (C1-C4) alkylenedioxy is linked at both ends thereof to adjacent carbons of the benzene moiety to which it is attached; R106, when it is not attached to a ring carbon which is adjacent to an oxy, thio or xe2x80x94Nxe2x80x94 ring atom, is a member independently selected, for each occurrence in partial Formulas (8.41) and (8.42), from the group consisting essentially of hydroxy; amino; N-mono- or N,N-di-(C1-C4) alkylamino; sulfo; and (C1-C4) alkoxy; and R106, when it is attached to a ring carbon which is adjacent to an oxy, thio or xe2x80x94Nxe2x80x94 ring atom, is a member independently selected, for each occurrence in partial Formulas (8.41) and (8.42), from the group consisting essentially of carboxy; hydroxy(C1-C4) alkyl; (C1-C4) alkoxy(C1-C4) alkyl; amino(C1-C4) alkyl; mono-Nxe2x80x94 and di-N,Nxe2x80x94(C1-C4) alkylamino(C1-C4) alkyl; morpholino(C1-C4) alkyl; 4-(C1-C4) alkyl-piperazin-1-yl(C1-C4) alkyl; carboxy(C1-C4) alkyl; (C1-C4) alkoxycarbonyl; sulfo(C1-C4) alkyl; and (C1-C4) alkyl;
where preferred embodiments comprise compounds wherein n is 0; and m is 1 and R105 is chloro resulting in quinazoline-(6-chloro-2,3-dihydro-1H-indol-1-yl)-methylamine compounds, e.g., bioisosteres of CP-292,597 of Formula (8.8), which may be represented by Formulas (8.43) and (8.44): 
xe2x80x83and pharmaceutically acceptable salts, prodrugs, and metabolites thereof;
where further details concerning predecessor catechol compounds, e.g., CP-292,597 compounds of Formula (8.8) are disclosed in Arnold International Pat. WO 95/23141, which is incorporated herein in its entirety;
(IV-D) R4a and R4b are taken together to form the moiety of partial Formula (8.45); 
wherein R96 and m are as defined under (IV-C) above, but are selected on an independent basis therefrom; W5 is xe2x80x94Yxe2x80x94CH2xe2x80x94; xe2x80x94CH2xe2x80x94Yxe2x80x94, or xe2x80x94Yxe2x80x94; where Y is O, S(O)q where q is an integer selected from 0, 1, and 2, or NR100 where R100 is hydrogen or (C1-C8) alkyl; and R99 is a group xe2x80x94ZR101xe2x80x94 where Z is joined to R101 through a bridging group (CH2)p where p is an integer selected from 0, 1 and 2; and Z is a member independently selected from the group consisting essentially of xe2x80x94Vxe2x80x94CH2xe2x80x94, xe2x80x94Vxe2x80x94CF2xe2x80x94, xe2x80x94CH2xe2x80x94Vxe2x80x94, xe2x80x94CF2xe2x80x94Vxe2x80x94, and xe2x80x94Vxe2x80x94, where V is a hydrocarbyl group containing 0, 1, or 2 carbon atoms; carbonyl; xe2x80x94CH(OH)xe2x80x94; sulfonamide; amide; xe2x80x94Oxe2x80x94; xe2x80x94S(O)qxe2x80x94; and xe2x80x94NR102 where R102 is hydrogen or (C1-C4) alkyl; and R101 is optionally substituted (C3-C7) cycloalkyl; or an optionally substituted 5,6,7,8,9, or 10-membered carbocyclic or heterocyclic moiety where said carbocyclic moiety is a member independently selected from the group consisting essentially of phenyl; benzyl; indene; naphthalene; tetralin; decalin; cyclopentyl; cyclohexyl; and cycloheptyl; and said heterocyclic moiety is a member independently selected from the group consisting essentially of furan; dioxolane; thiophene; pyrrole; imidazole; pyrrolidine; pyran; pyridine; pyrimidine; morpholine; piperidine; oxazoline; oxazolidine; thiazole; thiadiazole; benzofuran; indole; isoindole; quinazoline; quinoline; and isoquinoline; or R99 is a group xe2x80x94ZR101xe2x80x94 where Z is xe2x80x94NR102, and xe2x80x94NR102 and R101 together form a 5, 6, 7, 8, 9, or 10-membered heterocyclic moiety as defined under R101 above;
where preferred embodiments comprise compounds wherein R99 is in the para position with respect to W5; W5 is NR102 where R102 is hydrogen; and R99 is a member selected from the group consisting essentially of benzyl; phenoxy; and benzyloxy; e.g., a bioisostere represented by Formulas (8.46) and (8.47): 
and pharmaceutically acceptable salts, prodrugs, and metabolites thereof, and
where further details concerning predecessor catechol compounds, e.g., of Formula (8.10) are disclosed in Hudson et al. International Pat. WO 96/09294, which is incorporated herein by reference in its entirety.
(V) Bioisostere Replacement Compounds Active As PDE4 Inhibitors
Since the recognition that cyclic adenosine phosphate (AMP) is an intracellular second messenger, inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized, and their selective inhibition has led to improved drug therapy. More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release and airway smooth muscle relaxation. Thus, compounds that inhibit PDE type IV, but which have poor activity against other PDE types, inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects. TNF has also been recognized as being involved in many infectious and auto-immune diseases, and it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock.
This particular embodiment of the present invention relates to compounds having therapeutic usefulness based on their activity as phosphodiesterase-4 inhibitors, comprising an indazole-for-catechol bioisosteric replacement wherein said therapeutic usefulness is equivalent to or an improvement over the same activity possessed by the corresponding catechol-containing predecessor compound. In a preferred embodiment of this aspect of the present invention, the indazole-for-catechol bioisostere replacement compounds are therapeutically useful in treating asthma.
The indazole replacement bioisostere compounds of the present invention are useful in treating or preventing one or members selected from the groups of diseases and conditions consisting essentially of (1) inflammatory comprising: joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthtis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis, and Crohn""s disease; (2) respiratory comprising: asthma, acute respiratory distress syndrome, chronic pulmonary inflammatory disease, bronchitis, chronic obstructive airway disease, and silicosis; (3) infectious comprising: sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, fever and myalgias due to bacterial, viral or fungal infection, and influenza; (4) immune comprising: autoimmune diabetes, systemic lupus erythematosis, graft vs. host reaction, allograft rejections, multiple sclerosis, psoriasis, and allergic rhinitis; and (5) general comprising: bone resorption diseases; reperfusion injury; cachexia secondary to infection or malignancy; cachexia secondary to human acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection, or AIDS related complex (ARC); keloid formation; scar tissue formation; type 1 diabetes mellitus; and leukemia; wherein said compounds are inhibitors of phosphodiesterase isozyme 4 (PDE4).
Especially important among the above-recited diseases and conditions which may be treated or prevented using the compounds of the present invention are the inflammatory diseases and conditions and the respiratory diseases and conditions. Among the inflammatory diseases and conditions which are especially significant with regard to successful treatment or prevention using the compounds of the present invention comprise: joint inflammation, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease. Among the respiratory diseases and conditions which are especially significant with regard to successful treatment or prevention using the compounds of the present invention comprise: asthma, acute respiratory distress syndrome, and bronchitis.
Accordingly, a further embodiment of the present invention relates in particular to indazole-for-catechol bioisostere replacements active as PDE4 inhibitors, especially inhibitors useful in treating asthma and other respiratory and inflammatory diseases and conditions, comprising a compound of Formulas (9.0) and (9.1): 
and to pharmaceutically acceptable salts thereof, wherein:
RC5 is a member independently selected from the group consisting essentially of hydrogen; hydroxy; xe2x80x94Oxe2x80x94(C1-C4) alkyl; xe2x80x94Oxe2x80x94(C1-C4) alkyl(C1-C2) alkoxy; and xe2x80x94Oxe2x80x94(C1-C4) alkyl-morpholino;
RA5 is a member independently selected from the group consisting essentially of hydrogen, (C1-C9) alkyl; xe2x80x94(CH2)n(C3-C10) cycloalkyl wherein n is an integer selected from 0, 1, and 2; (C1-C6) alkoxy(C1-C6) alkyl; (C2-C6) alkenyl; xe2x80x94(CH2)n(C3-C9) heterocyclyl wherein n is an integer selected from 0, 1, and 2; and xe2x80x94(Z1)b(Z2)c(C6-C10) aryl wherein b and c are integers independently selected from 0 and 1, Z1 is (C1-C6) alkylene or (C2-C6) alkenylene, and Z2 is O, S, SO2, or NR119; and further wherein said heterocyclyl is a member independently selected from the group consisting essentially of acridinyl; benzimidazolyl; benzodioxolane; 1,3-benzodioxol-5-yl; benzo[b]furanyl; benzo[b]thiophenyl; benzoxazolyl; benzthiazolyi; carbazolyl; cinnolinyl; 2,3-dihydrobenzofuranyl; 1,3-dioxane; 1,3-dioxolane; 1,3-dithiane; 1,3-dithiolane; furanyl; imidazolidinyl; imidazolinyl; imidazolyl; 1H-indazolyl; indolinyl; indolyl; 3H-indolyl; isoindolyl; isoquinolinyl; isothiazolyl; isoxazolyl; morpholinyl; 1,8-naphthyridinyl; oxadiazolyl; 1,3-oxathiolane; oxazolidinyl; oxazolyl; oxiranyl; parathiazinyl; phenazinyl; phenothiazinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; pteridinyl; pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolo[1,5-c]triazinyl; pyrazolyl; pyridazinyl; pyridyl; pyrimidinyl; pyrimidyl; pyrrolyl; pyrrolidinyl; purinyl; quinazolinyl; quinolinyl; 4H-quinolizinyl; quinoxalinyl; tetrazolidinyl; tetrazolyl; thiadiazolyl; thiazolidinyl; thiazolyl; thienyl; thiomorpholinyl; triazinyl; and triazolyl; wherein said aryl is a carbocyclic moiety which is a member independently selected from the group consisting essentially of benzyl; cis- and trans-decahydronaphthalenyl; 2,3-1H-dihydroindenyl (indanyl); indenyl; 1-naphthalenyl; 2-naphthalenyl; phenyl; and 1,2,3,4-tetrahydronaphthalenyl; wherein said alkyl, alkenyl, alkoxyalkyl, heterocyclyl, and aryl moieties defining said RA5 groups are substituted by 0 to 3 substituents where each said substituent comprises a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; hydroxy; (C1-C5) alkyl; (C2-C5) alkenyl; (C1-C5) alkoxy; (C3-C6) cycloalkoxy; mono-, di-, and tri-fluoromethyl; nitro; xe2x80x94C(xe2x95x90O)OR119, xe2x80x94C(xe2x95x90O)NR119R120, xe2x80x94NR119R120 and xe2x80x94S(xe2x95x90O)2NR119R120;
RB5 is a member independently selected from the group consisting essentially of hydrogen; (C1-C9) alkyl; (C2-C3) alkenyl; phenyl; (C3-C7) cycloalkyl; and (C3-C7) cycloalkyl(C1-C2) alkyl; wherein said alkyl, alkeny) and phenyl moieties defining said RB 5 groups are substituted by 0 to 3 substituents where each said substituent comprises a member independently selected from the group consisting essentially of methyl; ethyl; mono-, di-, and tri-fluoromethyl; and bromo, chloro, or fluoro;
R5a and R5b are independently selected from the group consisting essentially of hydrogen and hereinafter recited substituents, provided that one, but not both of R5a and R5b must be independently selected as hydrogen, wherein said substituents comprise moieities of partial Formulas (9.2); (9.3); (9.4); and (9.5): 
wherein the dashed lines in partial Formulas (9.2) and (9.3) independently and optionally represent a single or double bond, provided that in partial Formula (9.2) both dashed lines cannot both represent double bonds at the same time;
m is an integer selected from 0, 1, 2, 3, and 4, and when 2, may apply to a single carbon atom on the ring;
R113 is a member selected from the group consisting essentially of H; bromo, chloro, or fluoro; cyano; (C2-C4) alkynyl substituted by 0 or 1 substituent where said substituent is a member selected from the group consisting essentially of phenyl, pyridyl and pyrimidinyl; (C1-C4) alkyl substituted by 0 to 6 bromo, chloro, or fluoro; xe2x80x94CH2NHC(xe2x95x90O)C(xe2x95x90O)NH2; cyclopropyl substituted by 0 or 1 substituent where said substituent is a member selected from the group consisting essentially of R121; R127; CH2OR119; NR119R120; CH2NR119R120; C(xe2x95x90O)OR119; C(xe2x95x90O)NR119R120; Cxe2x89xa1CR121; C(Z)H; and xe2x80x94CHxe2x95x90CR121R121; provided that R113 is H in formula (9.2) when the dashed line for the ring carbon atom of R113 attachment represents a double bond;
R114 is a member selected from the group consisting essentially of H; R116; C(Y)R124; C(xe2x95x90O)OR124; C(Y)NR127R124; CN; C(NR127)NR127R124; C(NOR119)R124; C(xe2x95x90O)NR119NR119C(xe2x95x90O)R119; C(xe2x95x90O)NR119NR127R124; C(NOR124)R119; C(NR119)NR127R124; C(NR124)NR119R120; C(NCN)NR127R124, C(NCN)S(C1-C4) alkyl; CR119R120OR124, CR119R120SR124, CR119R120S(O)nR125 where n is an integer selected from 0, 1, and 2; CR119R120NR124R127; CR119R120NR127S(xe2x95x90O)2R15; CR119R120NR127C(Y)R124; CR119R120NR127C(xe2x95x90O)OR125; CR119R120NR127C(Y)NR127R124; CR119R120NR127C(NCN)NR127R124; CR119R120NR127C(CR119NO2)S(C1-C4) alkyl; CR119R120C(xe2x95x90O)OR125; CR119R120C(Y)NR127R124; CR119R120C(NR127)NR127R124; CR119R120CN; CR119R120C(NOR120)R124; CR119R120C(NOR124)R120; CR119R120NR127C(NR127)S(C1-C4) alkyl; CR119R120NR127C(NR127)NR127R124; CR119R120NR127C(xe2x95x90O)C(xe2x95x90O)NR127R124; CR119R120NR127C(xe2x95x90O)C(xe2x95x90O)OR124; tetrazolyl; thiazolyl; imidazolyl; imidazolidinyl; pyrazolyl; thiazolidinyl; oxazolyl; oxazolidinyl; triazolyl; isoxazolyl; oxadiazolyl; thiadiazolyl; CR119R120(tetrazolyl); CR119R120(thiazolyl); CR119R120(imidazolyl); CR119R120(imidazolidinyl); CR119R120(pyrazolyl); CR119R120(thiazolidinyl); CR119R120(oxazolyl); CR119R120(oxazolidinyl); CR119R120(triazolyl); CR119R120(isoxazolyl); CR119R120(oxadiazolyl); CR119R120(thiadiazolyl); CR119R120(morpholinyl); CR119R120(piperidinyl; CR119R120(piperazinyl); and CR119R120(pyrrolyl); where the recited heterocyclic groups and moieties for said R114 are substituted by 0 to 3 R124 substituents;
R115 is a member selected from the group consisting essentially of R119; OR119; xe2x80x94CH2OR119; cyano; C(xe2x95x90O)R119; C(xe2x95x90O)OR119; C(xe2x95x90O)NR119R120; and NR119R120; provided that R115 is absent when the dashed line in Formula (9.2) represents a double bond;
or R114 and R115 are taken together to form xe2x95x90O or xe2x95x90R118;
or R115 is hydrogen and R114 is OR124; SR124; S(O)nR125, where n is an integer selected from 0, 1, and 2; S(xe2x95x90O)2NR127R124; NR127R124; NR124C(xe2x95x90O)R119; NR127C(Y)R124; NR127C(xe2x95x90O)OR125; NR127C(Y)NR127R124; NR127S(xe2x95x90O)2NR127R124; NR127C(NCN)NR127R124; NR127S(xe2x95x90O)2R125; NR127C(CR119NO2)NR127R124; NR127C(NCN)S(C1-C4) alkyl; NR127C(CR119NO2)S(C1-C4) alkyl; NR127C(NR127)NR127R124; NR127C(xe2x95x90O)C(xe2x95x90O)NR127R124; and NR127C(xe2x95x90O)C(xe2x95x90O)OR124;
R116 is a member independently selected from the group consisting essentially of methyl and ethyl substituted by 0 to 5 bromo, chloro, or fluoro, wherein m may be 2 with respect to a single ring carbon atom to which R116 is attached;
R117 is a member independently selected from the group consisting essentially of OR124; SR124; SO2NR127R124; NR127R124; NR124C(xe2x95x90O)R119; NR127C(Y)R124; NR127C(xe2x95x90O)OR125; S(O)nR12 where n is an integer selected from 0, 1, and 2; OS(xe2x95x90O)2R122; OR122; OC(xe2x95x90O)NR123R122; OC(xe2x95x90O)R123; OC(xe2x95x90O)OR123; O(CR122R123)mOR122 where m is an integer selected from 0, 1, and 2; CR119R120OR124; CR119R120NR127R124; C(Y)R124; C(xe2x95x90O)OR124; C(Y)NR127R124; CN; C(NR127)NR127R124; C(NOR119)R124; C(xe2x95x90O)NR119NR119C(xe2x95x90O)R119; C(xe2x95x90O)NR119NR127R124; C(NOR124)R119; C(NR119)NR127R124; C(NR124)NR119R120; C(NCN)NR127R124; C(NCN)S(C1-C4) alkyl; tetrazolyl; thiazolyl; imidazolyl; imidazolidinyl; pyrazolyl; thiazolidinyl; oxazolyl; oxazolidinyl; triazolyl; isoxazolyl; oxadiazolyl; and thiadiazolyl; where the recited heterocyclic groups are substituted by 0 to 3 substituents where said substituent is R124;
R118 is a member independently selected from the group consisting essentially of xe2x80x94NR125; xe2x80x94NCR119R120(C2-C6) alkenyl; xe2x80x94NOR124; xe2x80x94NOR129; xe2x80x94NOCR119R120(C2-C6) alkenyl; xe2x80x94NNR119R124; xe2x80x94NNR119R129; xe2x80x94NCN; xe2x80x94NNR119C(Y)NR119R124; xe2x80x94C(CN)2; xe2x80x94CR124CN; xe2x80x94CR124C(xe2x95x90O)OR119; xe2x80x94CR124C(xe2x95x90O)NR119R124; xe2x80x94C(CN)NO2; xe2x80x94C(CN)C(xe2x95x90O)O(C1-C4) alkyl; xe2x80x94C(CN)OC(xe2x95x90O)O(C1-C4) alkyl; xe2x80x94C(CN)(C1-C4) alkyl; xe2x80x94C(CN)C(xe2x95x90O)NR119R124; 2-(1,3-dithiane), 2-(1,3-dithiolane), dimethylthio ketal, diethylthio ketal, 2-(1,3-dioxolane), 2-(1,3-dioxane), 2-(1,3-oxathiolane); dimethyl ketal and diethyl ketal;
R119 and R120 are each a member independently selected from the group consisting essentially of hydrogen and (C1-C4) alkyl substituted by 0 to 3 fluorine atoms;
R121 is a member independently selected from the group consisting essentially of fluoro and R120;
R122 is a member independently selected from the group consisting essentially of (C1-C6) alkyl; (C2-C3) alkenyl; (C3-C7) cycloalkyl; (C3-C7) cycloalkyl(C1-C2) alkyl; (C6-C10) aryl; and (C3-C9) heterocyclyl; where said aryl and heterocyclyl are as defined under RA5 above; and where said R122 groups are substituted with 0 to 3 substituents independently selected from the group consisting essentially of methyl; ethyl; mono-, di-, and tri-fluoromethyl; and bromo, chloro, or fluoro;
R123 is a member independently selected from the group consisting essentially of hydrogen and R122;
R124 is a member independently selected from the group consisting essentially of hydrogen and R125; or when R124 and R127 appear together as NR127R124 then R127 and R124 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring optionally containing one additional heteroatom selected from O, N and S;
R125 is a member independently selected from the group consisting essentially of (C1-C6) alkyl and xe2x80x94(CR119R120)nR126, where n is an integer selected from 0, 1, and 2 and R126 and said (C1-C6) alkyl are substituted by 0 to 3 substituents where each said substituent is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; nitro; cyano; NR120R127; C(xe2x95x90O)R119; OR119; C(xe2x95x90O)NR120R127; OC(xe2x95x90O)NR120R127; NR127C(xe2x95x90O)NR127R120; NR127(xe2x95x90O)R120; NR17C(xe2x95x90O)O(C1-C4) alkyl; C(NR127)NR127R120; C(NCN)NR127R120; C(NCN)S(C1-C4) alkyl; NR127C(NCN)S(C1-C4) alkyl; NR127C(NCN)NR127R120; NR127S(xe2x95x90O)2(C1-C4) alkyl; S(O)n(C1-C4) alkyl; where n is an integer selected from 0, 1, and 2; NR127C(xe2x95x90O)C(xe2x95x90O)NR127R120, NR127C(xe2x95x90O)C(xe2x95x90O)R127; thiazolyl; imidazolyl; oxazolyl; pyrazolyl; triazolyl; tetrazolyl; and (C1-C2) alkyl substituted with 0 to 3 fluorine atoms;
R126 is a member independently selected from the group consisting essentially of (C3-C7) cycloalkyl; pyridyl; pyrimidyl; pyrazolyl; imidazolyl; triazolyl; pyrrolyl; piperazinyl; piperidinyl; morpholinyl; furanyl; thienyl; thiazolyl; quinolinyl; naphthyl; and phenyl;
R127 is a member independently selected from the group consisting essentially of OR119 and R120;
R128 is a member independently selected from the group consisting essentially of H; C(Y)R124; C(xe2x95x90O)OR124; C(Y)NR127R124; CN; C(NR127)NR127R124; C(NOR119)R124; C(xe2x95x90O)NR119NR119C(xe2x95x90O)R119; C(xe2x95x90O)NR119NR127R124; C(NOR124)R119; C(NR119)NR127R124; C(NR124)NR119R120; C(NCN)NR127R124; C(NCN)S(C1-C4) alkyl; CR119R120OR124; CR119R120SR124; CR119R120S(O)nR125, where n is an integer selected from 0, 1, and 2; CR119R120NR124R127; CR119R120NR127S(xe2x95x90O)2R125; CR119R120NR127C(Y)R124; CR119R120NR127C(xe2x95x90O)OR125; Cr119R120NR127C(Y)NR127R124; CR119R120NR127C(NCN)NR127R124; CR119R120NR127C(CR9NO2)S(C1-C4) alkyl; tetrazolyl; thiazolyl; imidazolyl; imidazolidinyl; pyrazolyl; thiazolidinyl; oxazolyl; oxazolidinyl; triazolyl; isoxazolyl; oxadiazolyl; thiadiazolyl; wherein said recited heterocyclic groups are substituted by 0 to 3 substituents where each said substituent is independently selected from the group consisting essentially of R124;
R129 is a member independently selected from the group consisting essentially of xe2x80x94C(xe2x95x90O)R12; xe2x80x94C(xe2x95x90O)NR119R124; xe2x80x94S(xe2x95x90O)2R125; and xe2x80x94S(xe2x95x90O)2NR119R124;
Y is O or S; and,
Z is O; NR127; NCN; C(xe2x80x94CN)2; CR119CN; CR119NO2; CR119C(xe2x95x90O)OR119; CR119C(xe2x95x90O)NR119R120; C(xe2x80x94CN)C(xe2x95x90O)O(C1-C4) alkyl); and C(xe2x95x90CN)C(xe2x95x90O)NR119R120;
(V-B)
xe2x80x94OR, said substituents defining R5a and R5b comprise:
a member selected from the group consisting essentially of R229; xe2x80x94C(xe2x95x90O)NR222(CHR222)mC(xe2x95x90O)NR222O(CH2)q(C6-C10) aryl); xe2x80x94C(xe2x95x90NR242)NH(CH2)p(C6-C10) aryl; xe2x80x94C(xe2x95x90O)NR218(CHR222)mC(xe2x95x90O)NR222(CH2)pOR222; xe2x80x94C(xe2x95x90O)NR222(CHR222)mS(C1-C4) alkyl; xe2x80x94C[xe2x95x90NOC(xe2x95x90O)R235]R236; xe2x80x94CR227R228CHR238NR219SO2(CH2)pA; xe2x80x94CR227R228CHR238NR219P(xe2x95x90O)(OR222)C(xe2x95x90O)(C1-C4) alkyl; xe2x80x94CR227R238CHR238NR219P(xe2x95x90O)[(C1-C4) alkoxy]2, xe2x80x94Z3xe2x80x94R217; and xe2x80x94(CR227R228)mNR219(C(O))qR220 wherein p is an integer selected from 0, 1, and 2; m is an integer selected from 1, 2, 3, 4, 5, and 6; and q is an integer selected from 1 and 2;
xe2x80x94OR, said substituents defining R5a and R5b comprise a moiety of partial Formulas (9.6) through (9.14), inclusive: 
wherein in said partial Formulas (9.6)-(9.14), the structures of partial Formulas (9.11) and (9.12) are attached to the nucleus of Formula (9.0) or (9.1) at carbons 5, 6, or 7 of said partial Formulas (9.6) and (9.7); the dashed line in partial Formulas (9.8) and (9.9) indicates a single bond or double bond, except that R316 is absent in formulas (9.8) and (9.9) where said dashed line indicates a double bond; n is an integer selected from 0, 1, and 2; p is an integer selected from 0, 1, 2, 3, 4, 5, and 6; and m is an integer selected from 0, and 1;
R213 is a member independently selected from the group consisting essentially of xe2x80x94C(xe2x95x90O)N(CH3)(OCH3) and xe2x80x94(CH2)nOH, where n is an integer selected from 0, 1, 2, 3, and 4;
R214 and R215 are independently selected from the group consisting essentially of H; ethyl; xe2x80x94CO2H; and xe2x80x94C(xe2x95x90O)NHOH;
R216 is a member independently selected from the group consisting essentially of H; hydroxy; (C1-C6) alkyl; (C1-C6) alkoxy; xe2x80x94OC(xe2x95x90O)(C1-C6) alkyl and xe2x80x94OC(xe2x95x90O)(C6-C10) aryl;
R217 is a member independently selected from the group consisting essentially of (C6-C10) aryl and a 5- to 10-membered heterocyclyl, wherein said R217 groups are substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluroro; trifluoromethyl; cyano; nitro; xe2x80x94CO2R222, (C1-C4) alkoxy; xe2x80x94OC(xe2x95x90O)(C1-C4) alkyl; xe2x80x94NR222C(xe2x95x90O)(C1-C4) alkyl; xe2x80x94C(xe2x95x90O)NH2; xe2x80x94C(xe2x95x90O)NHOH; xe2x80x94C(xe2x95x90O)O(C1-C4) alkyl; (C1-C4) alkyl; xe2x80x94S(O)nR222 where n is an integer selected from 0, 1, and 2; benzoyl; xe2x80x94NR222R223, xe2x80x94OR222, (C1-C6) alkanoyl; xe2x80x94Y1xe2x80x94(C6-C10) aryl; xe2x80x94C(xe2x95x90O)O(C6-C10) aryl; xe2x80x94NH(C6-C10) aryl; xe2x80x94C(xe2x95x90O)NH(C6-C10) aryl; xe2x80x94C(xe2x95x90O)NR222O(CH2)n(C6-C10) aryl, where n is an integer selected from 1, 2, and 3; and xe2x80x94SO2NH(C6-C10) aryl;
R218 is a member independently selected from the group consisting essentially of H; (C1-C6) alkyl; and xe2x80x94(CH2)n(C6-C10) aryl, where n is an integer selected from 0, 1, 2, 3, and 4;
R219 is a member independently selected from the group consisting essentially of H; xe2x80x94OR222; xe2x80x94(CH2)mA; and xe2x80x94CH2O(CH2)mA, where m is an integer selected from 0, 1, and 2;
R220 is a member independently selected from the group consisting essentially of (C1-C4) alkyl; xe2x80x94OR222; xe2x80x94CR222R223OR222; xe2x80x94CR222R223NR222R223; xe2x80x94CR222(OR223)CR222R223OR222; 2,2-dimethyl-1,3-dioxolan-4-yl; xe2x80x94NR222C(xe2x95x90O)NR222R223, xe2x80x94S(CR222R223)nCHnCH3 where n is an integer selected from 0, 1, 2, 3, 4, and 5; xe2x80x94NR222(CH2)q(pyridyl) where q is an integer selected from 0 and 1; xe2x80x94P(xe2x95x90O)[(C1-C4) alkoxy)]2; xe2x80x94NR222R223; xe2x80x94NR222OR223; xe2x80x94NR222NR223R221, xe2x80x94NR222CH2R224; xe2x80x94OCH2NR222C(xe2x95x90O)R224; xe2x80x94OCH2C(xe2x95x90O)NR225R226, xe2x80x94OCHR222OC(xe2x95x90O)(C1-C4) alkyl; xe2x80x94OCHR222C(xe2x95x90O)(C1-C3) alkoxy; xe2x80x94O(CH2)mR221; and xe2x80x94NR222(CH2)mR221 where m is an integer selected from 0, 1, and 2;
R221 is a member independently selected from the group consisting essentially of H and A;
each R222 and R223 is a member independently selected from the group consisting essentially of H and (C1-C4) alkyl;
R224 is a member independently selected from the group consisting essentially of methyl and phenyl;
R225 is a member independently selected from the group consisting essentially of H; methyl; ethyl; and xe2x80x94CH2CH2OH;
R226 is a member independently selected from the group consisting essentially of H; methyl; ethyl; CH2C(xe2x95x90O)NH2; and xe2x80x94CH2CH2OH;
each R227 is a member independently selected from the group consisting essentially of H; hydroxy; cyano; halo; (C1-C3) alkyl; (C1-C3) alkoxy; xe2x80x94NR222R223; xe2x80x94C(xe2x95x90O)OR222; xe2x80x94C(xe2x95x90O)R222; xe2x80x94CHxe2x95x90CR222R223; xe2x80x94Cxe2x89xa1CR222; xe2x80x94CH2NR222R223; xe2x80x94CH2OR222; xe2x80x94C(xe2x95x90O)NR222R223; xe2x80x94C(Y5)H; and xe2x80x94CH2NR12C(xe2x95x90O)C(xe2x95x90O)NR222R223; provided that when R227 is hydroxy then R228 is H or (C1-C4) alkyl;
each R228 is a member independently selected from the group consisting essentially of H; fluoro; cyano; and (C1-C4) alkyl; where said methyl is substituted by 0 to 3 substituents each comprising a fluorine atom;
or R227 and R228 are taken together to form an oxo (xe2x95x90O) moiety;
R229 is a member independently selected from the group consisting essentially of phenyl; naphthyl; pyrrolyl; furanyl; thienyl, oxazolyl; pyridinyl; pyrimidinyl; pyridazinyl; quinolinyl; isoquinolinyl; 5,6,7,8-tetrahydroquinolinyl; and 5,6,7.8-tetrahydroisoquinolinyl, where said R229 groups, except said phenyl, are substituted by 0 to 3 substituents R233, and wherein said phenyl R229 group is substituted by 0 to 3 substituents independently selected from R233 and R234;
R230 is a member independently selected from the group consisting essentially of xe2x80x94C(xe2x95x90O)R231; xe2x80x94C(xe2x95x90O)C(xe2x95x90O)R231, xe2x80x94C(xe2x95x90O)C(Y2)C(xe2x95x90O)R231 and a moiety of partial Formula (9.15): 
xe2x80x83wherein
R231 is a member independently selected from the group consisting essentially of H; xe2x80x94OR232; xe2x80x94NHR232; xe2x80x94NHOH; xe2x80x94NHNH2; xe2x80x94(CH2)nY3(phenyl) and xe2x80x94(CH2)nY3(pyridyl) where n is an integer selected from 0, 1, 2, 3, and 4;
R232 is a member independently selected from the group consisting essentially of H; (C1-C8) alkyl; xe2x80x94(CH2)nY3(phenyl) and xe2x80x94(CH2)nY3(pyridyl) where n is an integer selected from 0, 1, 2, 3, and 4;
each R233 is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; (C1-C6) alkyl; (C1-C7) alkoxy; (C2-C6) alkylenedioxy; trifluoromethyl; xe2x80x94NR222R223; nitro; xe2x80x94C(NR222)NR222R223; xe2x80x94C(xe2x95x90O)NR222R223C(xe2x95x90O)R222; xe2x80x94C(NOR222)R223; xe2x80x94C(NCN)NR222R223; xe2x80x94C(NCN)SR222; xe2x80x94(CH2)m(CN) where m is an integer selected from 0, 1, 2, and 3; hydroxy; xe2x80x94C(xe2x95x90O)R222, xe2x80x94C(xe2x95x90O)NR222OR223; xe2x80x94C(xe2x95x90O)NR222NR222R223; xe2x80x94OC(xe2x95x90O)NR222R223; xe2x80x94NR222C(xe2x95x90O)R222; xe2x80x94C(xe2x95x90O)C(xe2x95x90O)NR222R223; xe2x80x94CO2R222; xe2x80x94SO2R222; xe2x80x94SO2NR222R223; xe2x80x94C(xe2x95x90O)NR222R223; xe2x80x94NR222SO2R223; and xe2x80x94NR222C(xe2x95x90O)NR222R223;
each R234 is a member independently selected from the group consisting essentially of imidazolyl; pyrazolyl; triazolyl; tetrazolyl; oxazolyl; isoxazolyl; oxadiazolyl; thiadiazolyl; thiazolyl; oxazolidinyl; thiazolidinyl; and imidazolidinyl, where each of said foregoing R234 substituents is substituted by 0 to 3 substituents R233;
R235 is a member independently selected from the group consisting essentially of xe2x80x94NR222R223; xe2x80x94NH(C6-C10) aryl; (C1-C6) alkoxy; and (C6-C10) aryloxy;
R236 is a member independently selected from the group consisting essentially of H; (C1-C6) alkyl and xe2x80x94(CH2)mY4(phenyl) where m is an integer selected from 0, 1, 2, 3, and 4 and the phenyl moiety of said xe2x80x94(CH2)mY4(phenyl)R236 group is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; xe2x80x94OR222; (C1-C6) alkanoyloxy; (C6-C10) aryloxy; xe2x80x94NR222R223; xe2x80x94NH(C6-C10) aryl; and xe2x80x94NHC(xe2x95x90O)(C1-C4) alkyl;
each R237 is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; xe2x80x94(CH2)pNR222C(xe2x95x90O)CH3 where p is an integer selected from 1, 2, 3, 4, and; (C1-C4) alkoxy; nitro; cyano; xe2x80x94NR222R223; xe2x80x94CO2R222; xe2x80x94OR222; xe2x80x94C(Y1)NR222R223; xe2x80x94NR222C(NCN)S(C1-C3) alkyl; xe2x80x94NR222C(NCN)NR222R223; xe2x80x94NR222C(xe2x95x90O)NR222R223; xe2x80x94NR222C(xe2x95x90O)C(xe2x95x90O)NR222R223; xe2x80x94C(xe2x95x90NR222)NR222R223; xe2x80x94S(O)mCH3 where m is an integer selected from 0, 1, and 2; xe2x80x94C(xe2x95x90NR222)S(C1-C3) alkyl; xe2x80x94NR222SO2(C1-C3) alkyl; xe2x80x94OC(xe2x95x90O)R222; xe2x80x94OC(xe2x95x90O)NR222R223; xe2x80x94NR222SO2CF3; xe2x80x94NR222C(xe2x95x90O)C(xe2x95x90O)OR222; xe2x80x94NR222C(xe2x95x90O)R222; xe2x80x94NR222C(xe2x95x90O)OR222; imidazolyl; thiazolyl; oxazolyl; pyrazolyl; triazolyl: and tetrazolyl;
R238 is a member independently selected from the group consisting essentially of H; fluoro; cyano; and (C1-C2) alkyl, where said alkyl is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; xe2x80x94C(xe2x95x90O)NR222R223; and xe2x80x94C(xe2x95x90O)OR222;
R239 is a member independently selected from the group consisting essentially of phenyl substituted by 0 to 2 substituents independently selected from xe2x80x94NR222R223, nitro, halo, xe2x80x94OR222, xe2x80x94NHR240, xe2x80x94NR240R241, and xe2x80x94C(xe2x95x90O)OR222;
each R240 and R241 is a member independently selected from the group consisting essentially of (C1-C8) alkyl and (C2-C8) alkenyl;
R242 is pyridin-4-yl substituted by 0 to 2 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; and (C1-C4) alkyl;
each A is a member independently selected from the group consisting essentially of (C1-C6) alkyl; pyridyl; morpholinyl; piperidinyl; imidazolyl; thienyl; pyrimidyl; thiazolyl; triazolyl; quinolinyl; phenyl; and naphthyl; wherein the foregoing A groups are substituted with 0 to 3 substituents R237; or A is xe2x80x94(CH2)qS(C1-C4) alkyl wherein q is an integer selected from 1 and 2;
W is a member independently selected from the group consisting essentially of O; NOH; NNH2; NOC(xe2x95x90O)CH3; and NNHC(xe2x95x90O)CH3;
Y1 is O or S;
Y2 is O, NOH or H2;
Y3 is a bond or xe2x80x94CHxe2x95x90CHxe2x80x94;
Y4 is a bond, O, S, or xe2x80x94NHxe2x80x94;
Y5 is a member independently selected from the group consisting essentially of O; NR222; NOR222; NCN; C(CN)2; CR222NO2; CR222C(xe2x95x90O)OR222; CR222C(xe2x95x90O)NR222R223; C(CN)NO2; C(CN)C(xe2x95x90O)OR222; and C(CN)C(xe2x95x90O)NR222R223; and
Z3 is a member independently selected from the group consisting essentially of xe2x80x94NR222xe2x80x94; xe2x80x94(CH2)mxe2x80x94; xe2x80x94CH2C(xe2x95x90O)NHxe2x80x94; xe2x80x94NHCH2C(xe2x95x90O)xe2x80x94; xe2x80x94CH2C(Y1)CH2xe2x80x94; xe2x80x94CHxe2x95x90CHxe2x80x94; xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH(Y1H)xe2x80x94; xe2x80x94C(Y1)xe2x80x94; xe2x80x94CH2C(Y1); xe2x80x94C(Y1)CH2xe2x80x94; xe2x80x94C(Y1)C(Y1)xe2x80x94; xe2x80x94CH2NR222xe2x80x94; xe2x80x94CH2xe2x80x94Y1xe2x80x94; xe2x80x94C(Y1)NR218(CHR222)nxe2x80x94; xe2x80x94NR218C(Y1)(CHR222)nxe2x80x94; xe2x80x94NHCH2xe2x80x94; xe2x80x94Y1xe2x80x94CH2xe2x80x94; xe2x80x94SOCH2xe2x80x94; xe2x80x94CH2SOxe2x80x94; xe2x80x94SO2CH2xe2x80x94; xe2x80x94CH2SO2xe2x80x94; xe2x80x94OC(Y1)xe2x80x94; xe2x80x94Nxe2x95x90Nxe2x80x94; xe2x80x94NHSO2xe2x80x94; xe2x80x94SO2NHxe2x80x94; xe2x80x94C(Y1)C(Y1)NHxe2x80x94; xe2x80x94NHC(xe2x95x90O)Oxe2x80x94; xe2x80x94OC(xe2x95x90O)NHxe2x80x94; and xe2x80x94NHC(xe2x95x90O)NHxe2x80x94; wherein for said Z3 moieties n is an integer selected from 0, 1, 2, 3, and 4; and m is an integer selected from 1, 2, and 3;
(V-C)
xe2x80x94OR said substituents defining R5a and R5b comprise: a member independently selected from the group consisting essentially of 2-oxo-4-pyrrolyl; pyrazolyl; 2-oxo-3,4-dihydro-5-pyrimidyl; 2-oxo-3,4-dihydro-4-pyrimidyl; 2-oxo-tetrahydro-4-pyrimidyl; 2-oxo-tetrahydro-5-pyrimidyl; 2oxo-4-pyrimidyl; and 2-oxo-5-pyrimidyl; wherein each of said R2a and R2b groups is substituted by 0, 1, 2, 3, or 4 R236 groups;
xe2x80x94OR, said substituents defining R5a and R5b comprise a moiety of partial Formulas (9.16) through (9.35), inclusive: 
wherein, in said partial Formulas (9.16)-(9.35), q is an integer selected from 0 and 1 in partial Formula (9.17); n is an integer selected from 0, 1, and 2 in partial Formula (9.18); and the dashed lines appearing in formulas (9.17), (9.19), (9.22), (9.23), (9.24), (9.25) and (9.30) represent a double bond or a single bond;
X1 is O or S;
X2, in partial Formula (9.26) and where the dashed line in partial Formula (9.25) represents a double bond, is a member independently selected from the group consisting essentially of CR335; CR336; CR346; and COC(xe2x95x90O)NR339R342; or, where the dashed line in formula (9.25) represents a single bond, X2 is a member independently selected from the group consisting essentially of CR335R339; CR336R339; and CR346R339;
X3 is a member independently selected from the group consisting essentially of C(xe2x95x90Z3); C(S); and CR336R340;
X4 is a member independently selected from the group consisting essentially of xe2x80x94(CH2)mxe2x80x94 where m is an integer selected from 0, 1, and 2;
X5 is a bond or xe2x80x94CH2xe2x80x94;
X6 is a member independently selected from the group consisting essentially of xe2x80x94CH2xe2x80x94 and xe2x80x94C(xe2x95x90O)xe2x80x94;
R333 is a member independently selected from the group consisting essentially of H; hydroxy; (C1-C4) alkoxy; xe2x80x94CHR337(O)q(CH2)mA where q is an integer selected from 0 and 1, and m is an integer selected from 0, 1, and 2;
R334 is a member independently selected from the group consisting essentially of H; hydroxy; (C1-C4) alkyl; (C1-C2) alkoxy; xe2x80x94OC(xe2x95x90O)CH3; (C2-C3) alkenyl; and phenyl(C1-C2) alkyl-;
R335 is a member independently selected from the group consisting essentially of H; hydroxy; xe2x80x94(CH2)mA where m is an integer selected from 0, 1, and 2; (C1-C6) alkyl; and (C2-C3) alkanoyl; where said alkyl group is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; nitro; xe2x80x94NR340R341; xe2x80x94CO2R340; xe2x80x94OR340; xe2x80x94OC(xe2x95x90O)R340; xe2x80x94C(xe2x95x90O)R340; cyano; xe2x80x94C(xe2x95x90Y)NR340R341; xe2x80x94NR340C(xe2x95x90Y)NR340R341; xe2x80x94NR340C(xe2x95x90Y)R340; xe2x80x94NR340C(xe2x95x90O)OR340; xe2x80x94C(NR340)NR340OR341; xe2x80x94C(NCN)NR340R341; xe2x80x94C(NCN)SR340; xe2x80x94NR340SO2R340; xe2x80x94S(O)mR340, where m is an integer selected from 0, 1, and 2; xe2x80x94NR340SO2CF3; xe2x80x94NR340C(xe2x95x90O)C(xe2x95x90O)NR340R341; xe2x80x94NR340C(xe2x95x90O)C(xe2x95x90O)OR340; imidazolyl; and 1-(NHR340)-2-imidazolyl;
each R336 is a member independently selected from the group consisting essentially of H; bromo, chloro, or fluoro; cyano; R343; cyclopropyl substituted by 0 or 1 substituent independently selected from the group consisting essentially of R339; xe2x80x94OR340; xe2x80x94CH2OR340; xe2x80x94NR340R342; xe2x80x94CH2NR340R342; xe2x80x94C(xe2x95x90O)OR340; xe2x80x94C(xe2x95x90O)NR340R342; xe2x80x94CHxe2x95x90CR339R339; xe2x80x94Cxe2x89xa1CR339; and xe2x80x94C(xe2x95x90Z3)H;
R337 is a member independently selected from the group consisting essentially of H; xe2x80x94C(xe2x95x90O)R338; imidazolyl; pyrazolyl; triazolyl; tetrazolyl; oxazolyl; isoxazolyl; oxadiazolyl; thiadiazolyl; thiazolyl; oxazolidinyl; thiazolidinyl; and imidazolidinyl;
each R338 is a member independently selected from the group consisting essentially of xe2x80x94OR340; xe2x80x94NR340R342; and xe2x80x94R343;
each R339 is a member independently selected from the group consisting essentially of H; bromo, chloro, or fluoro; and (C1-C4) alkyl substituted by 0 to 3 fluorine atoms;
each R340 and R341 is a member independently selected from the group consisting essentially of hydrogen and (C1-C4) alkyl;
each R342 is a member independently selected from the group consisting essentially of xe2x80x94OR340 and xe2x80x94R340;
R343 is (C1-C4) alkyl;
each R344 is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; nitro; cyano; xe2x80x94NR340R346; xe2x80x94NR346R342; xe2x80x94C(xe2x95x90Z3)R338; S(O)mR343 where m is an integer selected from 0, 1, and 2; xe2x80x94OR342; xe2x80x94OC(xe2x95x90O)NR340R342; xe2x80x94C(NR342)NR340R342; xe2x80x94C(NR340)SR343; xe2x80x94OC(xe2x95x90O)CH3; xe2x80x94C(NCN)NR340R342; xe2x80x94C(S)NR340R342; xe2x80x94NR342C(xe2x95x90O)R347; xe2x80x94C(xe2x95x90O)R347; oxazolyl; imidazolyl; thiazolyl; pyrazolyl; triazolyl; and tetrazolyl;
each R345 is a member independently selected from the group consisting essentially of hydrogen and (C1-C4) alkyl substituted by 01 to 3 fluorine atoms;
each R346 is a member independently selected from the group consisting essentially of H; xe2x80x94R343; xe2x80x94C(xe2x95x90O)R343; xe2x80x94C(xe2x95x90O)C(xe2x95x90O)R338; xe2x80x94C(xe2x95x90O)NR340R342; xe2x80x94S(O)mR343 where m is an inter selected from 0, 1, and 2; xe2x80x94C(NCN)SR343; xe2x80x94C(NCN)R343; xe2x80x94C(NR342)R343; xe2x80x94C(NR342)SR343; and xe2x80x94C(NCN)NR340R342;
each R347 is a member independently selected from the group consisting essentially of xe2x80x94R343; xe2x80x94C(xe2x95x90O)R343; oxazolidinyl; oxazolyl; thiazolyl; pyrazolyl; triazolyl; tetrazolyl; imidazolyl; imidazolidinyl; thiazolidinyl; isoxazolyl; oxadiazolyl; thiadiazolyl; morpholinyl; piperidinyl; piperazinyl; and pyrrolyl; where each of said recited R347 heterocyclic groups is substituted by 0 to 2 (C1-C2) alkyl groups;
R348 is a member independently selected from the group consisting essentially of H; (C1-C5) alkyl; (C2-C5) alkenyl; benzyl; and phenethyl;
R349 is a member independently selected from the group consisting essentially of H; (C1-C5) alkyl; (C1-C5) alkanoyl; and benzoyl;
R350 is a member independently selected from the group consisting essentially of H; (C1-C4) alkyl; carboxy; aminocarbonyl; (C1-C6) alkyl substituted by 0 or 1 carboxy, xe2x80x94(CH2)mC(xe2x95x90O)(C1-C6) alkoxy; or xe2x80x94(CH2)m(C6-C10) aryl; where m is an integer selected from 0, 1, and 2;
R351 is a member independently selected from the group consisting essentially of H; (C1-C6) alkyl; xe2x80x94C(xe2x95x90Y)R352; xe2x80x94C(xe2x95x90Y)NH35; xe2x80x94C(xe2x95x90O)OR352; and xe2x80x94(CH2)nX7(pyridyl) where n is an integer selected from 0, 1, 2, 3, 4, and to 5; and X7 is a bond or xe2x80x94CHxe2x95x90CHxe2x80x94; and where said pyridyl moiety is substituted by 0 or 1 bromo, chloro, or fluoro;
R352 is a member independently selected from the group consisting essentially of (C1-C6) alkyl (C3-C8) cycloalkyl; xe2x80x94(CH2)m(C6-C10) aryl; and xe2x80x94(CH2)nX7(pyridyl) where n is selected from 0, 1, 2, 3, 4, and 5; and X7 is a bond or xe2x80x94CHxe2x95x90CHxe2x80x94; and where said pyridyl moiety is substituted by 0 or 1 bromo, chloro, or fluoro;
R353 is a member independently selected from the group consisting essentially of H; xe2x80x94R345; (C1-C3) alkyl substituted by 0 or 1 substituent hydroxy, or (C1-C3) alkyoxy(C1-C3) alkyl;
R354 is a member independently selected from the group consisting essentially of H; xe2x80x94R345; carboxy; (C1-C3) alkyoxy(C1-C3) alkyl-; (C3-C7) cycloalkyl; and (C1-C5) alkyl substituted by 0 or 1 xe2x80x94NR340R341;
or R353 and R354 are taken together to form xe2x80x94CH2OCH2OCH2xe2x80x94;
R355 is a member independently selected from the group consisting essentially of H; hydroxy; (C1-C4) alkyl substituted by 0 or 1 substituent comprising a member independently selected from the group consisting essentially of hydroxy; xe2x80x94C(xe2x95x90O)R340; xe2x80x94NR340R341; xe2x80x94(CH2)mNHC(xe2x95x90O)R340; xe2x80x94(CH2)mNHC(xe2x95x90O)R343; xe2x80x94(CH2)mCO2R340; xe2x80x94(CH2)mC(xe2x95x90O)NR340R341; xe2x80x94(CH2)mC(xe2x95x90O)N(OH)R340; xe2x80x94(CH2)mSO2NR340R341; xe2x80x94(CH2)mPO3H2; xe2x80x94(CH2)mSO2NHC(xe2x95x90O)R343; and xe2x80x94(CH2)mSO2NHC(xe2x95x90O)(phenyl), where m is an integer selected from 0, 1, 2, 3, and 4;
R356 is a member independently selected from the group consisting essentially of H; (C1-C4) alkyl; phenyl; xe2x80x94NR340R341; and xe2x80x94NR340(C1-C4) alkanoyl;
R357 is a member independently selected from the group consisting essentially of xe2x80x94R340; xe2x80x94CH2CO2R343; and xe2x80x94CH2C(xe2x95x90O)NR340R341;
R358 is a member independently selected from the group consisting essentially of xe2x80x94C(xe2x95x90O)R340; xe2x80x94C(xe2x95x90O)(C6-C10) aryl; xe2x80x94C(xe2x95x90O)(C3-C9) heteroaryl; xe2x80x94CO2R340; xe2x80x94C(xe2x95x90O)NR340R341; cyano; nitro; xe2x80x94CH2OH; xe2x80x94NR340SO2R340; xe2x80x94NHSO2(C6-C10) aryl; xe2x80x94NHCO2(C1-C4) alkyl; xe2x80x94NR340C(xe2x95x90O)R340; and xe2x80x94NHCO2(C6-C10) aryl;
R359 is a member independently selected from the group consisting essentially of xe2x80x94R345; cyano; carboxy; formyl; xe2x80x94C(xe2x95x90O)R340; and (C1-C4) alkanoyl;
R360 is a member independently selected from the group consisting essentially of cyano; xe2x80x94NR340R341; xe2x80x94SO2(C1-C4) alkyl; xe2x80x94SO2(C6-C10) aryl; xe2x80x94C(xe2x95x90O)R340; xe2x80x94C(xe2x95x90O)(C6-C10) aryl; xe2x80x94C(xe2x95x90O)(C3-C9) heteroaryl; xe2x80x94C(xe2x95x90O)NR340R341; and xe2x80x94CO2R340;
R361 and R362 is each a member independently selected from the group consisting essentially of H; cyano; nitro; xe2x80x94CO2R340; xe2x80x94C(xe2x95x90O)NR340R341; xe2x80x94CH2OH; xe2x80x94C(xe2x95x90O)R340; xe2x80x94NHCO2R340; and xe2x80x94NHSO2R340;
A is a member independently selected from the group consisting essentially of pyridyl; morpholinyl; piperidinyl, imidazolyl; thienyl; pyrimidyl; thiazolyl; phenyl; and naphthyl; where each of said A groups is substituted by 0 to 2 substituents R344 or by 1 substituent R345;
Z3 a member independently selected from the group consisting essentially of O; xe2x80x94NR342; NOR340; N(CN); C(CN)2; CR340NO2; CR340C(xe2x95x90O)OR343; CR340C(xe2x95x90O)NR340R341; C(CN)NO2; C(CN)C(xe2x95x90O)OR343; and C(CN)C(xe2x95x90O)NR340R341; and,
Y is O or S;
(V-D)
xe2x80x94OR said substituents defining R5a and R5b comprise a moiety of partial Formula (9.36): 
xe2x80x83wherein
the broken line indicates a single or double bond;
X1 is xe2x80x94CR472R473xe2x80x94 where said broken line indicates a single bond; or xe2x80x94CR473xe2x80x94 where said broken line indicates a double bond;
X2 is xe2x80x94CR475R477R478xe2x80x94 or xe2x80x94C(xe2x95x90NOR481)R482xe2x80x94 where said broken line indicates a single bond; or xe2x80x94CR477R478 where said broken line indicates a double bond;
R472 is a member independently selected from the group consisting essentially of H; hydroxy; bromo, chloro, or fluoro; and xe2x80x94OR479;
each R473 is a member independently selected from the group consisting essentially of cyano; cyanomethyl; benzyloxy; xe2x80x94R475; xe2x80x94CO2R475; xe2x80x94CO2(CH2)n(C6-C10) aryl; xe2x80x94C(Y)NR475R476; xe2x80x94C(Y)NR475(CH2)n(C6-C10) aryl; xe2x80x94(CH2)n(C6-C10) aryl; and xe2x80x94(CH2)n(5- to 10-membered heteroaryl); where n is an integer selected from 0, 1, 2, and 3; each R473 group is substituted by 0 to 3 substituents R474; and each R473 group is substituted by 0 or 1 substituent R480;
each R474 is a member independently selected from the group consisting essentially of bromo, chloro, or fluoro; cyano; nitro; (C1-C6) alkyl; (C2-C6) alkenyl; xe2x80x94OR475; (C3-C7) cycloalkoxy; xe2x80x94NR475R476; xe2x80x94NR475OR476; xe2x80x94S(O)mR475 where m is an integer selected from 0, 1, and 2; xe2x80x94CO2R475, xe2x80x94C(xe2x95x90O)R475; xe2x80x94SO2NR475R476; xe2x80x94C(xe2x95x90O)NR475R476; xe2x80x94CR475R476SO2NR475R476; xe2x80x94CR475R476C(xe2x95x90O)NR475R476; xe2x80x94NHSO2R476; xe2x80x94NHSO2NR475R476; xe2x80x94NHC(xe2x95x90O)NR475R476; xe2x80x94NHC(xe2x95x90O)(C1-C6) alkyl; and xe2x80x94NHC(xe2x95x90O)O(C1-C6) alkyl);
each R475 and R476 is a member independently selected from the group consisting essentially of H; and (C1-C6) alkyl;
R477 is a member independently selected from the group consisting essentially of xe2x80x94R473; 2-oxo-pyridyl; 3-oxo-pyridyl; 4-oxo-pyridyl; 2-oxo-pyrrolyl; 4-oxo-thiazolyl; 4-oxo-piperidyl; 2-oxo-quinolyl; 4-oxo-quinolyl; 1-oxo-isoquinolyl; 4-oxo-oxazolyl; 5-oxo-pyrazolyl; 5-oxo-isoxazolyl; and 4-oxo-isoxazolyl; where each of said R477 groups is substituted by 0 to 3 substituents R474;
R478 is a member independently selected from the group consisting essentially of xe2x80x94R475; cyano; xe2x80x94(CH2)p(C6-C10) aryl; and xe2x80x94(CH2)p(5- to 10-membered heteroaryl); where p is an integer selected from 1, 2, and 3; and where each said R478 group is substituted by 0 to 3 substituents R474;
R479 is a member independently selected from the group consisting essentially of formyl; carbamoyl; thiocarbamyl; (C1-C6) alkyl; (C2-C6) alkenyl; (C1-C4) alkoxy(C1-C4) alkyl-; and (C1-C6) alkanoyl; where said alkyl moieties of each of said R479 groups is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; hydroxy; and (C1-C4) alkoxy;
R480 is a member independently selected from the group consisting essentially of cyclobutyl; cyclopentyl; cyclohexyl; 2-cyclobuten-1-yl; 2-cyclopenten-1-yl; 3-cyclopenten-1-yl; 2,4-cyclopentadien-1-yl; 3,5-cyclohexadien-1-yl; pyrrolyl; pyrrolidinyl; dioxolanyl; imidazolyl; oxazolyl; imidazolidinyl; pyrazolyl; pyrazolidinyl; pyranyl; piperidinyl; 1,4-dioxanyl; morpholinyl; 1,4-dithianyl; thiomorpholinyl; piperazinyl; 1,3,5-trithianyl; oxazinyl; isoxazinyl; oxathiazinyl; and oxadiazinyl; where each of said R480 groups is substituted by 0 to 2 (C1-C2) alkyl;
R481 is a member independently selected from the group consisting essentially of H; (C1-C6) alkyl; (C2-C6) alkenyl; (C2-C6) alkynyl; xe2x80x94C(Y)NR475R476; xe2x80x94C(Y)NH(C6-C10) aryl; xe2x80x94C(Y)(C1-C6) alkoxy; xe2x80x94C(Y)(C6-C10) aryloxy; and xe2x80x94C(Y)(C1-C6) alkyl);
R482 is a member independently selected from the group consisting essentially of phenyl and pyridinyl; where each of said R482 groups is substituted by 0 to 3 substituents independently selected from the group consisting essentially of bromo, chloro, or fluoro; (C1-C4) alkyl; hydroxy; (C1-C4) alkoxy; xe2x80x94NR475R476; and xe2x80x94S(O)mR475, where m is an integer selected from 0, 1, and 2; and,
Y is O or S;
(V-E)
xe2x80x94OR, said substituents defining R5a and R5b comprise a moiety of partial Formulas (9.37) through (9.49), inclusive: 
Preferred compounds of Formula (9.0) or (9.1) where R5a and R5b are as defined under (V-D) above, include those wherein R1 is ethyl and R is cyclopentyl, cyclohexyl, or (C6-C10)aryl.
Other preferred compounds of Formula (9.0) or (9.1) include those wherein R473 is xe2x80x94(CH2)n(C6-C10)aryl or xe2x80x94(CH2)n(5- to 10-membered heteroaryl), where n is an integer selected from 0, 1, 2, and 3; and, more preferably, wherein R473 is phenyl or pyridin-4-yl.
Specific embodiments of the compounds of Formula (9.0) or (9.1) where R5a and R5b are as defined under (V-A) include those wherein R is cyclopentyl or cyclohexyl, R1 is (C1-C2) alkyl, preferably ethyl, one of R5a and R5b is hydrogen and the other is a substituent of Formula (9.2) where the dashed line represents a single bond, m is 0, R113 and R114 are in a cis relationship to each other, R113 is cyano, R115 is hydrogen, and R114 is carboxy, xe2x80x94CH2OH, or xe2x80x94CH2C(xe2x95x90O)NH2.
Other specific embodiments of the compounds of Formula (9.0) or (9.1) include those wherein R is phenyl substituted by fluoro, R1 is (C1-C2) alkyl, preferably ethyl, one of R5a and R5b is hydrogen and the other is a substituent of Formula (9.2) where the dashed line represents a single bond, R113 is cyano, and R115 and R114 are both hydrogen.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, means saturated monovalent hydrocarbon radicals which are straight or branched moieties containing from one to six, preferably one to four, carbon atoms.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, unless otherwise indicated, means O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is defined above.
The term xe2x80x9calkenylxe2x80x9d, as used herein, unless otherwise indicated, means unsaturated alkyl groups having one or more double bonds wherein xe2x80x9calkylxe2x80x9d is defined above.
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein, unless otherwise indicated, means saturated monovalent cyclo hydrocarbon radicals containing from three to seven carbon atoms, preferably five or six carbon atoms, including such specific radicals as cyclobutyl, cyclopentyl and cycloheptyl.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, means an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, comprising a carbocyclic moiety which is a member independently selected from the group consisting essentially of benzyl; cis- and trans-decahydronaphthalenyl; 2,3-1H-dihydroindenyl (indanyl); indenyl; 1-naphthalenyl; 2-naphthalenyl; phenyl; and 1,2,3,4-tetrahydronaphthalenyl; and preferably means phenyl.
The term xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d, as used herein, unless otherwise indicated, means aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N. Included within this meaning are heterocyclic groups which are benzo-fused ring systems and ring systems substituted with an oxo moiety. Included within the scope of this definition are the following specific groups: acridinyl; benzimidazolyl; benzodioxolane; 1,3-benzodioxol-5-yl; benzo[b]furanyl; benzo[b]thiophenyl; benzoxazolyl; benzthiazolyl; carbazolyl; cinnolinyl; 2,3-dihydrobenzofuranyl; 1,3-dioxane; 1,3-dioxolane; 1,3-dithiane; 1,3-dithiolane; furanyl; imidazolidinyl; imidazolinyl; imidazolyl; 1H-indazolyl; indolinyl; indolyl; 3H-indolyl; isoindolyl; isoquinolinyl; isothiazolyl; isoxazolyl; morpholinyl; 1,8-naphthyridinyl; oxadiazolyl; 1,3-oxathiolane; oxazolidinyl; oxazolyl; oxiranyl; parathiazinyl; phenazinyl; phenothiazinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; pteridinyl; pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolo[1,5-c]triazinyl; pyrazolyl; pyridazinyl; pyridyl; pyrimidinyl; pyrimidyl; pyrrolyl; pyrrolidinyl; purinyl; quinazolinyl; quinolinyl; 4H-quinolizinyl; quinoxalinyl; tetrazolidinyl; tetrazolyl; thiadiazolyl; thiazolidinyl; thiazolyl; thienyl; thiomorpholinyl; triazinyl; and triazolyl.
With reference to the R114 substituent of partial Formula (9.2) of Formula (9.0) or (9.1), the (C3-C9) heterocyclic group can be attached to the (C1-C6) alkyl group by a nitrogen or, preferably, a carbon atom. An example of a C3 heterocyclic group is thiazolyl, and an example of a C9 quinolizinyl; heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl. Examples of aromatic heterocyclic groups which are preferred are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl and thiazolyl. A preferred heterocyclic group having a fused benzene ring is benzimidazolyl.
Where heterocyclic groups are specifically recited or covered as substituents for the compound of Formula (9.0) or (9.1) under (V-A), it is understood that all suitable isomers of such heterocyclic groups are intended. Thus, for example, in the definition of the substituent R114, the term xe2x80x9cthiazolylxe2x80x9d includes 2-, 4- or 5-thiazolyl; the term xe2x80x9cimidazolylxe2x80x9d includes 2-, 4- or 5-imidazolyl; the term xe2x80x9cpyrazolylxe2x80x9d includes 3-, 4- or 5-pyrazolyl; the term xe2x80x9coxazolylxe2x80x9d includes 2-, 4- or 5-oxazolyl; the term xe2x80x9cisoxazolylxe2x80x9d includes 3-, 4- or 5-isoxazolyl, and so on. Likewise, in the definition of substituent R116, the term xe2x80x9cpyridylxe2x80x9d includes 2-, 3- or 4-pyridyl.
Certain xe2x80x9caminalxe2x80x9d or xe2x80x9cacetalxe2x80x9d-like chemical structures within the scope of Formula (9.0) or (9.1) may be unstable. Such structures may occur where two heteroatoms are attached to the same carbon atom. For example, where R is (C1-C6) alkyl substituted by hydroxy, it is possible that the hydroxy may be attached to the same carbon that is attached to the nitrogen atom from which R extends. It is to be understood that such unstable compounds are not within the scope of the present invention.
Preferred compounds of Formula (9.0) or (9.1) under (V-A) include those wherein R5a quinolizinyl; or R5b is a group of the partial Formula (9.50) or (9.51): 
where for partial Formula (9.50) R113 and R114, especially where R114 is xe2x80x94OH, are cis with respect to each other; and for partial Formula (9.51) R116a, R116b, R116c and R116d are independently selected from the group consisting essentially of xe2x80x94H; xe2x80x94CH3; xe2x80x94CF3; xe2x80x94CHF2; and xe2x80x94CH2F;
Other preferred compounds of Formula (9.0) or (9.1) under (V-A) include those wherein R is a member independently selected from the group consisting essentially of cyclohexyl, cyclopentyl, cyclobutyl, methylenecyclopropyl, isopropyl, phenyl, and 4-fluoro-phenyl.
Other preferred compounds of Formula (9.0) or (9.1) under (V-A) include those wherein R1 is (C1-C2) alkyl substituted by 0 to 3 fluorine atoms, and, more preferably, those wherein R1 is ethyl.
Other preferred compounds of Formula (9.0) or (9.1) under (V-A) include those wherein one of R5a and R5b is hydrogen and the other is a group of partial Formula (9.2) wherein the dashed line attached to the ring carbon atom to which R113 is attached represents a single bond.
Other preferred compounds of Formula (9.0) or (9.1) under (V-A) include those wherein one of R5a and R5b is hydrogen and the other is a group of partial Formula (9.2) wherein the dashed line attached to the ring carbon atom to which R113 is attached represents a single bond and R113 is cyano.
Other preferred compounds of Formula (9.0) or (9.1) under (V-A) include those wherein one of R5a and R5b is hydrogen and the other is a group of partial Formula (9.2) wherein the dashed line attached to the ring carbon atom to which R113 is attached represents a single bond, m is 0 and R115 is hydrogen.
Other preferred compounds of Formula (9.0) or (9.1) under (V-A) include those wherein one of R5a and R5b is hydrogen and the other is a group of partial Formula (9.2) wherein the dashed line attached to the ring carbon atom to which R113 is attached represents a single bond; m is 0; R115 is hydrogen; and R114 is a member independently selected from the group consisting essentially of xe2x80x94OH; xe2x80x94CH2OH; xe2x80x94C(CH3)2OH; xe2x80x94C(xe2x95x90O)OH; xe2x80x94C(xe2x95x90O)OCH3; xe2x80x94C(xe2x95x90O)OCH2CH3; and xe2x80x94CH2C(xe2x95x90O)NH2.
Other more preferred compounds of Formula (9.0) or (9.1) under (V-A) include those wherein R is a member independently selected from the group consisting essentially of cyclobutyl, cyclopentyl, cyclohexyl, and 4-fluoro-phenyl; R1 is ethyl; one of R5a and R5b is hydrogen and the other is a group of partial Formula (9.51) wherein R113 is cyano; R115 is hydrogen; R114 is xe2x80x94OH; R113 and R114 are cis with respect to each other; and R116a, R116b, R116c and R116d are each a member independently selected from the group consisting essentially of xe2x80x94H; and xe2x80x94CH3;
Preferred compounds of Formula (9.0) or (9.1) include those wherein R1 is ethyl.
Other preferred compounds of Formula (9.0) or (9.1) include those wherein R is a member independently selected from the group consisting essentially of cyclohexyl; cyclopentyl; methylenecyclopropyl; isopropyl; phenyl; and 4-fluoro-phenyl.
Specific preferred compounds of Formula (9.0) or (9.1) under (V-A) include:
1-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-oxocyclohexanecarbonitrile;
Trans-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methyl ester;
Cis-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methyl ester;
Trans-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;
Cis-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;
1-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-oxocyclohexanecarbonitrile;
Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methyl ester;
Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methyl ester;
Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;
Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;
Cis-1-(1-cyclohexyl-3-ethyl-1H-indazole-6-yl)-4-hydroxymethylcyclohexanecarbonitrile;
Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid amide;
Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid amide;
Cis-1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-(1-hydroxy-1-methylethyl)cyclohexanecarbonitrile;
Cis-1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;
Cis-1-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]-4-hydroxycyclohexanecarbonitrile;
Cis-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;
Cis-1-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;
Cis-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydrox-4-methylcyclohexanecarbonitrile;
Trans-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-4-methylcyclohexanecarbonitrile;
Cis-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;
Trans-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid;
6-Bromo-3-ethyl-1-(4-fluorophenyl)-1H-indazole;
4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]-4-hydroxycyclohexanecarboxylic acid ethyl ester;
4-Cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohexanecarboxylic acid ethyl ester;
4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylic acid ethyl ester;
4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylic acid ethyl ester;
Cis-4-Cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohexanecarboxylic acid;
4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylic acid; and
4-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarboxylic acid.
The phrase xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of Formula (9.0) or (9.1). For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of carboxylic acid groups and hydrochloride salts of amino groups. Other pharmaceutically acceptable salts of amino groups are hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.
Certain species of above-desecribed compounds may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of Formula (9.0) or (9.1), and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of Formula (9.0) or (9.1), the invention includes the use of a racemate, a single enantiomeric form, a single diastereomeric form, or mixtures thereof. The compounds of Formula (9.0) or (9.1) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
Another embodiment of this aspect of the present invention relates to a pharmaceutical composition for the inhibition of PDE4 or the production of TNF in a mammal comprising a therapeutically effective amount of a therapeutically active composition of matter comprising a compound as above-desecribed, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.
Another embodiment of the present invention relates to a method for the inhibition of PDE4 or the production of TNF by administering to a patient a therapeutically effective amount of a therapeutically active composition of matter comprising a compound as above-desecribed or a pharmaceutically acceptable salt thereof.
Accordingly, the present invention also relates to method of treating or preventing a disease or condition in a mammal in need of such treatment wherein said disease or condition responds favorably to inhibition of PDE4 or production of TNF and is a member selected from the group consisting essentially of asthma; joint inflammation; rheumatoid arthritis; gouty arthritis; rheumatoid spondylitis; osteoarthritis; sepsis; septic shock; endotoxic shock, gram negative sepsis; toxic shock syndrome; acute respiratory distress syndrome; cerebal malaria; chronic obstructive pulmonary disease (COPD), including asthma, chronic bronchitis and pulmonary emphysema; silicosis; pulmonary sarcoidosis; bone resorption diseases; reperfusion injury; graft vs. host reaction; allograft rejections; fever and myalgias due to bacterial, viral or fungal infection including influenza; cachexia secondary to infection or malignancy; cachexia secondary to human acquired immune deficiency syndrome (AIDS); AIDS; HIV infection; ARC (AIDS related complex); keloid formation; scar tissue formation; Crohn""s disease; ulcerative colitis; pyresis; multiple sclerosis; type 1 diabetes mellitus; autoimmune diabetes; systemic lupus erythematosis; bronchitis; psoriasis; Bechet""s disease; anaphylactoid purpura nephritis; chronic glomerulonephritis; inflammatory bowel disease; leukemia; allergic rhinitis; and dermatitis, comprising administering to said mammal a therapeutically effective amount of a therapeutically active composition of matter comprising a compound of Formula (IA) or (IB), optionally together with a pharmaceutically acceptable carrier therfor.
The present invention further relates to a pharmaceutical composition for the prevention or treatment of the diseases and conditions enumerated above, especially including asthma, in a mammal, comprising a therapeutically effective amount of a compound according to Formula (9.0) or (9.1), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.
This invention further relates to a method of treating or preventing the foregoing specific diseases and conditions by administering to a patient a therapeutically effective amount of a compound of Formula (9.0) or (9.1), or a pharmaceutically acceptable salt thereof. In particular, the present invention includes compounds useful in treating or preventing one or members selected from the groups of diseases and conditions consisting essentially of (1) inflammatory diseases and conditions comprising: joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis, and Crohn""s disease; (2) respiratory diseases and conditions comprising: acute respiratory distress syndrome, chronic obstructive pulmonary disease (COPD) including asthma, chronic bronchitis, and pulmonary emphysema, acute bronchitis, and silicosis; (3) infectious diseases and conditions comprising: sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, fever and myalgias due to bacterial, viral or fungal infection, and influenza; (4) immune diseases and conditions comprising: autoimmune diabetes, systemic lupus erythematosis, graft vs. host reaction, allograft rejections, multiple sclerosis, psoriasis, and allergic rhinitis; and (5) other diseases and conditions comprising: bone resorption diseases; reperfusion injury; cachexia secondary to infection or malignancy; cachexia secondary to human acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection, or AIDS related complex (ARC); keloid formation; scar tissue formation; type 1 diabetes mellitus; and leukemia; wherein said compound comprises an inhibitor of PDE4.
Especially important among the above-recited diseases and conditions which may be treated or prevented using the compounds of the present invention are the inflammatory diseases and conditions and the respiratory diseases and conditions. Among the inflammatory diseases and conditions which are especially significant with regard to successful treatment or prevention using the compounds of the present invention comprise: joint inflammation, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease. Among the respiratory diseases and conditions which are especially significant with regard to successful treatment or prevention using the compounds of the present invention comprise: asthma, acute respiratory distress syndrome, and bronchitis.
The expression xe2x80x9ctreating or preventingxe2x80x9d, as used herein with regard to the administration of the compounds of the present invention for therapeutic purposes in the case of various members selected from the many groups of diseases and conditions specifically recited herein, is intended to denote both the therapeutic objective of said administration as well as the therapeutic results actually achieved by said administration. The extent of therapy accomplished by administration of the compounds of the present invention may range from an amelioration to a significant diminishing of the course of the disease involved, and beyond to active treatment of said disease, including a reversal of the disease process itself which is present. The higher or highest degrees of therapeutic effectiveness result in the prevention of any injury, damage, deterioration, or loss of body tissues or organs and basic body functions subsequent to the early stages of degeneration and decline in said body tissues or organs and basic body functions at the onset of the disease involved.
The expression xe2x80x9cthe early stages of degeneration and decline in body tissues or organs and basic body functionsxe2x80x9d is intended to mean the very beginning of the initial pathologic changes in said body tissues or organs and basic body functions which define and are the result of a disease process. Said pathologic changes with respect to tissues and organs include changes in the composition and cohesiveness; form and makeup; rigidity, strength, resilience, elasticity, conformational integrity and stability, density, tensile strength and other measures of physical quality; abundance and extent of its presence throughout the body; viability and regenerative capability on both a micro- and macro-level; and the ability to successfully resist various kinds of external stresses including mechanical force and invasion by microorganisms; of said tissues and organs from that present before the onset of said disease process, which result in a degradation and decline of the beneficial and necessary properties characterizing said tissues and organs.
Pathologic changes with respect to body functions are those which inherently arise from the changes above-described with respect to said tissues and organs, and which also, consequently, result in a degradation and decline in the beneficial and necessary performance which characterizes the normal and proper operation of said body functions. These pathologic changes, both with regard to tissues or organs and with respect to body functions, especially include improper repair of the above-discussed early stages of degeneration and decline.
Synthetic preparation of each and all of the above-described indazole-for-catechol bioisostere replacement compositions of matter does not usually start, of course, with a catechol compound. Direct preparation of an indazole per se using methods well known in the art of preparing organic compounds is usually the most straightforward and efficient method of preparing the bioisostere replacement compounds of the present invention. The technical literature is replete with suitable methods for carrying out such preparations. However, in order to better illustrate the manner in which bioisostere replacement compounds of the present invention may be prepared, there are set out below numerous reaction schemes and working examples for preparing indazole compounds types (II), (III) and (V) as described above, ie., bioisostere replacement compounds which are active as adrenergics, calcium channel blockers, and PDE4 inhibitors. Said reaction schemes are accompanied by an ongoing explanation of each step of the synthesis involved. Working examples in accordance with which these synthesis steps are carried out are also presented further below. Analogous synthesis methods may be carried out in order to prepare other compounds of the present invention, modifying where necessary starting materials and reactants.
Reaction Schemes 1-7 below illustrate the preparation of the compounds of the present invention of type (V): 
The compounds in the schematic representations above are numbered using Roman numerals in consecutive order, starting with II. These Roman numeral reference numbers are not necessarily related to the Roman numerals used elsewhere in defining the compounds of the present invention. Unless otherwise indicated, R and R1 in the reaction schemes are defined the same as elsewhere herein.
The preparation of indazole bioisostere replacement compounds of the present invention, especially those of Formula (9.0) or (9.1) can be carried out by one skilled in the art according to one or more of the synthetic methods outlined in Schemes 1-4 above and the examples referred to below. In Step 1 of Scheme 1, the carboxylic acid of Formula II, which is available from known commercial sources or can be prepared according to methods known to those skilled in the art, is nitrated under standard conditions of nitration (HON/H2SO4, 0xc2x0C.) and the resulting nitro derivative of Formula III is hydrogenated in Step 2 of Scheme 1 using standard hydrogenation methods (H2xe2x80x94Pd/C under pressure) at ambient temperature (20-25xc2x0 C.) for several hours (2-10 hours) to provide the compound of Formula IV. In Step 3 of Scheme 1, the amino benzoic acid of Formula IV is reacted with a base such as sodium carbonate under aqueous conditions and gently heated until mostly dissolved. The reaction mixture is chilled to a lower temperature (about 0xc2x0 C.) and treated with sodium nitrate in water. After about 15 minutes, the reaction mixture is slowly transferred to an appropriate container holding crushed ice and a strong acid such as hydrochloric acid. The reaction mixture is stirred for 10-20 minutes and then added, at ambient temperature, to a solution of excess tert-butyl thiol in an aprotic solvent such as ethanol. The reaction mixture is acidified to a pH of 4-5 through addition of an inorganic base, preferably saturated aqueous Na2CO3, and the reaction mixture is allowed to stir at ambient temperature for 1-3 hours. Addition of brine to the reaction mixture, followed by filtration, provides the sulfide of Formula V.
In Step 4 of Scheme 1, the sulfide of Formula V is converted to the corresponding indazole carboxylic acid of Formula VI by reacting the sulfide of Formula V with a strong base, preferably potassium teft-butoxide, in dimethyl sulfoxide (DMSO) at ambient temperature. After stirring for several hours (1-4 hours), the reaction mixture is acidified with a strong acid, such as hydrochloric or sulfuric acid, and then extracted using conventional methods. In Step 5 of Scheme 1, the indazole carboxylic acid of Formula VI is converted to the corresponding ester of Formula VII by conventional methods known to those skilled in the art. In Step 6 of Scheme 1, the compound of Formula VII is provided through alkylation of the ester of Formula VII by subjecting the ester to conventional alkylation conditions (strong base/various alkylating agents and, optionally, a copper catalyst such as CuBr2) in a polar aprotic solvent, such as tetrahydrofuran (THF), N-methylpyrrolidinone or dimethylformamide (DMF), at ambient or higher temperature (25-200xc2x0 C.) for about 6-24 hrs, preferably about 12 hours. In Step 7 of Scheme 1, the compound of Formula VIII is converted to the corresponding alcohol of IX by following conventional methods known to those skilled in the art for reducing esters to alcohols. Preferably, the reduction is effected through use of a metal hydride reducing agent, such as lithium aluminum hydride, in a polar aproptic solvent at a low temperature (about 0xc2x0 C.). In Step 8 of Scheme 1, the alcohol of Formula IX is oxidized to the corresponding aldehyde of Formula X according to conventional methods known to those skilled in the art. For example, the oxidation can be effected through use of a catalytic amount of tetrapropylammonium perrutenate and excess N-methylmorpholine-N-oxide, as described in J. Chem. Soc., Chem. Commun., 1625 (1987), in an anhydrous solvent, preferably methylene chloride.
Scheme 2 provides an alternative method of preparing the aldehyde of Formula X. In Step 1 of Scheme 2, the compound of Formula XI is nitrated using conventional nitration conditions (nitric and sulfuric acid) to provide the compound of Formula XII. In Step 2 of Scheme 2, the nitro derivative of Formula XII is reduced to the corresponding amine of Formula XIII according to conventional methods known to those skilled in the art. Preferably, the compound of Formula XII is reduced to the amine of Formula XIII using anhydrous stannous chloride in an anhydrous aprotic solvent such as ethanol. In Step 3 of Scheme 2, the amine of Formula XIII is converted to the corresponding indazole of Formula XIV by preparing the corresponding diazonium fluoroforates as described in A. Roe, Organic Reactions, Vol. 5, Wiley, New York, 1949, pp. 198-206, followed by phase transfer catalyzed cyclization as described in R. A. Bartsch and I. W. Yang, J. Het. Chem. 21, 1063 (1984). In Step 4 of Scheme 2, alkylation of the compound of Formula XIV is performed using standard methods known to those skilled in the art, e.g., strong base, polar aprotic solvent and an alkyl halide, to provide the N-alkylated compound of Formula XV. In Step 5 of Scheme 2, the compound of Formula XV is subjected to metal halogen exchange employing an alkyl lithium, such as n-butyl lithium, in a polar aprotic solvent, such as THF, at low temperature (xe2x88x9250xc2x0 C. to 100xc2x0 C., with xe2x88x9278xc2x0 C. being preferred) followed by quenching with DMF at low temperature and warming to ambient temperature to provide the aldehyde compound of Formula X.
Scheme 3 illustrates the preparation of a compound of Formula XXII which is a compound of Formula (9.0) or (9.1) wherein R5a or R5b is a ring moiety of Formula (9.2). In Step 1 of Scheme 3, the aldehyde moiety of the compound of Formula X is converted to an appropriate leaving group, such as a halogen, mesylate or another leaving group familiar to those skilled in the art, followed by reacting the resulting compound with sodium cyanate in a polar solvent such as DMF to provide the compound of Formula XVI. In Step 2 of Scheme 3, the compound of Formula XVI is reacted under basic conditions with methyl acrylate or related derivatives depending on the R5a or R5b group to be added, in an aprotic solvent such as ethylene glycol dimethyl ether (DME) at high temperature, preferably at reflux, to provide the compound of Formula XVII. In Step 3 of Scheme 3, the compound of Formula XVII is converted to the compound of Formula XVIII using a strong base, such as sodium hydride, and a polar aprotic solvent, such as DMF or THF, at elevated temperature, preferably at reflux.
In Step 4 of Scheme 3, the compound of Formula XVIII is decarboxylated using conventional methods, such as using sodium chloride in DMSO at a temperature of about 140xc2x0 C., to provide the compound of Formula XIX. In Step 5 of Scheme 3, derivatization of the compound of Formula XIX to the corresponding dithian-2-ylidine cyclohexane carbonitrile of Formula XX is done by reaction with 2-lithio-1,3-dithiane. In Step 5-a of Scheme 3, further derivatization of the compound of Formula XIX to the corresponding cyclohexane carbonitrile of Formula XXV which is para-substituted on the cyclohexane group with an hydroxyl moiety and an R4 substituent, e.g., methyl, is carried out by reacting the ketone with a nucleophilic reagent, e.g., an alkyllithium compound or a Grignard reagent in accordance with procedures well known in the art. In Step 5-b of Scheme 3, further derivatization of the compound of Formula XIX to the corresponding cyclohexane carbonitrile of Formula XXVI which is para-substituted on the cyclohexane group with an hydroxyl moiety, is carried out by reducing the ketone with, e.g., lithium aluminum hydride or sodium borohydride in accordance with procedures well known in the art. In Step 6 of Scheme 3, the compound of Formula XX is converted to the corresponding ester of Formula XXI using mercury (II) chloride and perchloric acid in a polar protic solvent such as methanol. In Step 7 of Scheme 3, the compound of Formula XXI is converted through hydrolysis to the corresponding carboxylic acid of Formula XXII using a standard method of hydrolysis, such as using aqueous sodium hydroxide in a polar solvent, or any of numerous existing hydrolysis methods known to those skilled in art as described in T. Green and P. G. M. Wets, Protecting Groups in Organic Synthesis, 2nd Edition, John Wiley and Sons, New York (1991). The synthetic steps described for Scheme 3 are analogous to the synthetic methods provided for the preparation of corresponding catechol-containing compounds in PCT published applications WO 93/19751 and WO 93/17949.
Other indazole bioisostere replacement compounds of the present invention, especially those of Formula (9.0) or (9.1) wherein one of R5a or R5b is selected from moieties (9.2), (9.3), (9.4) and (9.5), can be prepared from one or more of the intermediate compounds described in Schemes 1-3. In particular, the aldehyde of Formula X or the keto compound of Formula XIX can be used to prepare various indazole bioisostere replacement compounds of the present invention, especially those of Formula (9.0) or (9.1). Any of the various R5a or R5b moieties of formulas (9.2), (9.3), (9.4) or (9.5) can be introduced into one or more of the intermediate compounds referred to above using synthetic methods provided for corresponding non-indazole analogs in PCT published applications WO 93/19748, WO 93/19749, WO 93/09751, WO 93/19720, WO 93/19750, WO 95/03794, WO 95/09623, WO 95/09624, WO 95/09627, WO 95/09836, and WO 95/09837. For example, with reference to Step 1 of Scheme 4, the carboxylic acid of Formula XXII can be converted to the alcohol of Formula XXIII by reduction with various metal hydrides in a polar solvent as described in Example 9, referred to below, and in accordance with synthetic methods provided for corresponding non-indazole analogs in PCT published applications publication numbers WO 93/19747, WO 93/19749 and WO 95/09836. Further, with reference to Step 2 of Scheme 4, the carboxylic acid of Formula XXII can be converted to the corresponding carboxamide of Formula XXIV through conversion to an intermediate acid chloride using conventional synthetic methods, and then reacting the acid chloride with ammonia in an aprotic solvent. Other carboxamide analogs of Formula XXIV can be prepared through reaction of the acid chloride intermediate with various primary or secondary amines according to conventional methods known to those skilled in the art and as described in the PCT published applications referred to above.
Other indazole bioisostere replacement compounds of the present invention, especially those of Formula (9.0) or (9.1) can be prepared from the intermediate compound of Formula XIX in accord with synthetic methods provided for corresponding non-indazole analogs in the PCT published applications referred to above. Compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of partial Formula (9.2), and either R114 (R4) or R is H, can be prepared from the keto intermediate of Formula XIX by reaction with a base such as lithium diisopropylamine in a polar aprotic solvent, such as THF, and excess N-phenyltrifluoromethylsulfonamide as described in PCT published application WO 93/19749 for corresponding non-indazole analogs. Compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of partial Formula (9.2), R114 (R4) is hydrogen, and R115 (R5) is xe2x80x94CO2CH3 or xe2x80x94CO2H, can be prepared from the keto intermediate of Formula XIX through reaction with triflic anhydride in the presence of a tertiary amine base followed by reaction of the resulting triflate with (triphenylphosphine)palladium and carbon monoxide in the presence of an alcohol or amine to provide the methyl ester compounds of Formula (9.0) or (9.1) wherein R115 (R5) is xe2x80x94CO2CH3. The methyl ester compound can be hydrolyzed to obtain the corresponding carboxylic acid compound by employing standard methods for hydrolysis such as sodium or potassium hydroxide in aqueous methanol/tetrahydrofuran. Such synthetic methods are further described in PCT published application WO 93/19749 for corresponding non-indazole analogs.
Other indazole bioisostere replacement compounds of the present invention, especially those of Formula (9.0) or (9.1) can be prepared from the intermediate compound of Formula XIX in accord with synthetic methods described for corresponding non-indazole analogs in the published PCT applications referred to above. Compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of partial Formula (9.2), R115(R5) is hydrogen, and R114(R4) is hydroxy, can be prepared through reaction of the intermediate of Formula XIX with an appropriate reducing agent such as lithium borohydride, diamyl borane, lithium aluminum tris(tert-butoxide), or sodium borohydride in a suitable non-reacting solvent such as 1,2-dimethoxy ethane, THF or alcohol. Compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of Formula (9.2), R115 (R5) is hydrogen and R114 (R4) is xe2x80x94NH2, xe2x80x94NHCH3, or xe2x80x94N(CH3)2, can be prepared by reacting the intermediate of Formula XIX with an ammonium salt, such as ammonium formate, methylamine hydrochloride or dimethylamine hydrochloride, in the presence of sodium cyanoborohydride in an appropriate solvent such as alcohol.
Alternatively, compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of Formula (9.2), R114 (R4) is amino, and R115 (R5) is hydrogen, can be prepared by reacting the corresponding alcohol of Formula (9.0) or (9.1) where R114 (R4)xe2x95x90OH and R115 (R5)xe2x95x90H, with a complex of an azadicarboxylate ester in the presence of an imide or phthalimide followed by reaction in an alcoholic solvent such as ethanol. Compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of Formula (9.2), R115 (R5) is H, and R114 (R4) is xe2x80x94SR124 can be prepared by reacting the corresponding compound wherein R114 (R4) is a leaving group such as mesylate, tosylate, bromine or chlorine, with a metal salt of mercaptan such as NaSR124 in an appropriate aprotic solvent. Corresponding compounds of Formula (9.0) or (9.1) wherein R114 (R4) is xe2x80x94SH can be prepared by reacting the corresponding alcohol R114 (R4)xe2x95x90OH, with a complex of a phosphine, such as triphenyl phosphine, and an azidocarboxylate ester in the presence of thiolacetic acid followed by hydrolysis of the resulting thiolacetate. Furthermore, compounds of this structure wherein R114 (R4) is hydroxy can be interconverted using a standard alcohol inversion procedure known to those skilled in the art. The foregoing compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of Formula (9.2), R115 (R5) is hydrogen, and R114 (R4) is hydroxy, xe2x80x94SH or xe2x80x94NH2, can be converted to various other compounds of Formula (9.0) or (9.1) through one or more synthetic methods described in PCT published applications WO 93/19751 and WO 93/19749 for corresponding non-indazole analogs.
Compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of Formula (9.2) and the dashed line represents a double bond attached to the ring carbon atom to which substituent R113 (R3) is attached, can be prepared from the intermediate of Formula XIX by following one or more synthetic methods provided for the preparation of corresponding non-indazole analogs in PCT published application WO 93/19720. Compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of Formula (9.2), and R114 (R4) and R115 (R5) are taken together to form xe2x95x90O or xe2x95x90R118, wherein R118 is as defined above, can be prepared from the corresponding ketone intermediate of formula XIX following one or more synthetic methods provided for corresponding non-indazole analogs in PCT published application WO 93/19750. Other compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of Formula (9.2) and R114 (R4) and R115 (R5) are taken together as xe2x95x90R118 can be prepared from the intermediate of Formula XIX following one or more synthetic methods provided for the preparation of corresponding non-indazole analogs in PCT published application WO 93/19748.
Compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of Formula (9.3) can be prepared from one or more of the intermediates referred to above, such as the bromoindazole intermediate of Formula XV, following one or more synthetic methods provided for the preparation of corresponding non-indazole analogs in PCT published applications WO 95/09627, WO 95/09624, WO 95/09623, WO 95/09836 and WO 95/03794. Compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of Formula (9.4) can be prepared from the intermediate of Formula XV following one or more of synthetic methods provided for the preparation of corresponding non-indazole analogs in PCT published applications WO 95/09624 and WO 95/09837. Compounds of Formula (9.0) or (9.1) wherein R5a or R5b is a moiety of Formula (9.5) can be prepared from the bromoindazole intermediate of Formula XV employing one or more synthetic methods provided for the preparation of the corresponding catechol-containing analogs in PCT published applications WO 95/09627, WO 95/09623 and WO 95/09624.
Particularly preferred indazole bioisostere replacement compounds of the present invention are those represented by Formulas (9.51) and (9.52): 
A method for the preparation of the compound of Formula (I-ii) is described in further below-recited Example 23. It is also possible to prepare said compound in accordance with the synthesis method described in above-depicted Scheme 2 and Scheme 3, using as the starting material for said method the compound prepared as described in below-recited Example 20, and represented by Formula (9.53): 
The preferred compound depicted in Formula (9.51)above may be prepared in accordance with the synthesis methods described in above-depicted Scheme 1, Scheme 2, and Scheme 3, and as further detailed in the below-recited Examples. Another, preferred, method of preparing said compound may also be employed, and is represented in the following synthesis Scheme 5, which is a more generalized representation of the above-mentioned preferred method of preparing said above-described preferred compound of the present invention. 
As illustrated, the starting material of Formula XXVIII is reacted with a hydrazine of Formula XXIX and the in sivu product of Formula XXX is heated without separation to yield an indazole of Formula XXXI, which is in turn reacted with dicyanocyclohexane of Formula XXXII to yield the cyano-analog of said above-described preferred compound of Formula XXXIII.
In Step 1 of Scheme 5, the compound of Formula XXVIII is treated with a hydrazine derivative of Formula XXIX and an acid, preferably ammonium acetate, in a solvent such as heptane, tetrahydrofuran, xylenes, toluene, or mesitylene, or a mixture of two or more of the foregoing solvents, preferably toluene, to provide the compound of Formula XXX. In general, the compound of Formula XXX need not be separated or isolated from the reaction mixture.
In Step 2 of Scheme 5, the reaction mixture containing the compound of Formula XXX is heated at a temperature between about 75xc2x0 C. and about 200xc2x0 C., preferably between about 90xc2x0 and 120xc2x0 C., for a period of about 2 hours to 48 hours, preferably 12 hours, to provide the compound of Formula XXXI.
Alternatively, the process of Step 1 of Scheme 5 may be accomplished using a salt of the hydrazine derivative, such as the hydrochloride, hydrobromide, mesylate, tosylate, or oxalate salt of said compound, preferably the mesylate salt, which is reacted with a base, such as sodium or potassium acetate, in a solvent such as heptane, tetrahydrofuran, xylenes, toluene, or mesitylene, or a mixture of two or more of the foregoing solvents, preferably toluene.
In Step 3 of Scheme 5, the compound of Formula XXXI is treated with the compound of Formula XXXII in the presence of a base such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, or lithium 2,2,6,6-tetramethylpiperidine, preferably potassium bis(trimethylsilyl)amide, in a solvent such as tetrahydrofuran, toluene, or xylenes, preferably toluene, at a temperature between about 25xc2x0 C. and about 125xc2x0 C., preferably about 100xc2x0 C., for a period 1 hour to 15 hours, preferably 5 hours, to provide compound of Formula XXXIII.
In Step 4 of Scheme 5, the compound of Formula XXXIII is treated with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, or trifluoromthanesulfonic acid, preferably hydrochloric acid, in a solvent of the Formula XXXIV, i.e., R124xe2x80x94OH wherein R124 is as defined herein, e.g., (C1-C6) alkyl, such as methanol, ethanol, propanol, isopropanol, preferably ethanol, at a temperature between 0xc2x0 C. and 50xc2x0 C., preferably ambient temperature (20-25xc2x0 C.) for a period of 1 hour to 48 hours, preferably 14 hours, to provide a compound of Formula XXXV. In general, the compound of Formula XXXV need not to be separated or isolated from the reaction mixture.
In step 5 of Scheme 5, the compound of Formula XXXV is treated with water in a solvent such as toluene, ethyl acetate, dilsopropyl ether, methyl tert-butyl ether, or dichloromethane, preferably toluene, at a temperature between about 0xc2x0 C. and 50xc2x0 C., preferably ambient temperature (20-25xc2x0 C.) for a period of 1 hour to 24 hours, preferably 8 hours, to provide a compound of Formula XXXVI.
A particular version of the synthesis of Scheme 5 above carried out with reactants suitable for obtaining the preferred cyclohexanecarboxylic acid compound of the present invention, is illustrated below in Scheme 6: 
Scheme 7 set out below illustrates a procedure to facilitate the handling and purification of the indazole intermediate of Formula XXXI which is described above in reference to Scheme 5. In Step 1 of Scheme 7, the indazole of Formula XXXI is treated with an acid, such as hydrobromic, hydrochloric, or sulfuric acid, preferably hydrobromic acid, in a solvent such as toluene, xylenes, acetic acid, or ethyl acetate, preferably toluene, at a temperature ranging from 0xc2x0 C. to ambient temperature (20-25xc2x0 C.), preferably ambient temperature, to form a salt of the compound of Formula XXXVIII, wherein HX indicates the acid used to prepare the salt and X is the anion of said acid. The salt may be separated and purified according to methods familiar to those skilled in the art. In Step 2 of Scheme 7, the salt is converted back to the free base. In this step, the salt of the compound of Formula XXXVIII is treated with an aqueous base, such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate, preferably sodium hydroxide, in a solvent such as hexane, toluene, dichloromethane, diisopropyl ether, methyl tert-butyl ether, or ethyl acetate, preferably toluene, at a temperature ranging from 0xc2x0 C. to ambient temperature (20-25xc2x0 C.), preferably ambient temperature, for a period of 5 minutes to 1 hour, preferably 20 minutes, to provide the compound of Formula XXXI. 
The compounds of the Formulas XXVIII-XXXVIII may have asymmetric carbon atoms and therefore exist in different enantiomeric forms. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers may be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound, e.g., alcohol, separating the diastereomers and converting, e.g., hydrolyzing, the individual diastereomers to the corresponding pure enantiomers. The use of all such isomers, including diastereomer mixtures and pure enantiomers, are considered to be part of the present invention.
Further details concerning the above-identified synthesis methods which are preferred for preparing the above-recited preferred compound of the present invention may be found in copending provisional U.S. Ser. No. 60/064,211, filed Nov. 4, 1997, which is incorporated herein by reference in its entirety.
Reaction Schemes 8 and 9 illustrate the preparation of the compounds of the present invention of type (II), i.e., xcex11-adrenergic receptor antagonist compounds of type (II): 
The synthesis depicted in Scheme 8 may be carried out using conventional chemistry such as that described in J. Org. Chem., 44, 4609 (1979). This preparation leads to formation of the key indazole intermediate of Formula XLVI. The key intermediate of Formula XLVI is then reacted with a suitable reactant in order to produce the desired final product. The schematic representation of Scheme 9 shows preparation of a compound of type (II) of the present invention, especially one of the type of Formula (II-B) where R2a and R2b are taken together to form the moiety of partial Formula (6.26): 
where E is either N, resulting in a pyrimidinyl moiety and overall a quinazoline series of compounds; or is CH, resulting in a pyridyl moiety and overall a quinoline series of compounds.
More especially Scheme 9 demonstrates preparation of a compound of the type of Formula (II-B) where R25 and R26 are both hydrogen and R27 is a moiety of type (g) illustrated by partial Formula (6.32.3), 
where R39a is xe2x80x94C(xe2x95x90O)xe2x80x94R40 where R40 is 4-morpholino. Preparation of the final product of Formula XLIX in Scheme 9 entails use of the reactant of Formula XLVII. The reactant of Formula XLVII is prepared, in turn, using conventional chemistry, such as that referred to in WO 97/23462, which is incorporated herein by reference in its entirety.
Reaction Schemes 10 through 12 illustrate the preparation of the compounds of the present invention type (III), i.e., calcium channel antagonist compounds of Formula (III), especially those that are bioisoteres of verapamil. The known compound verapamil, which may be represented by Formula (7.0): 
The chemical structure of a total of six (6) verapamil bioisoteres is described further above, and the synthesis of three of these is described in the paragraphs which follow. The six (6) indazole-for-catechol bioisostere replacement embodiments of verapamil described above are based only or first vs. second indazole isomers and single vs. double replacement. A third possibility resulting in isomers occurs where there is both a double replacement and first and second indazole isomers, i.e., the first indazole isomer is on one end of the molecule and the second indazole isomer is at the opposite end of the same molecule. Where the molecule is asymmetrical as in the case of verapamil, two (2) additional bioisotere isomers result, giving an overall total of eight (8) verapamil bioisostere isomers.
The three verapamil bioisostere isomers whose preparation is illustrated herein are species based on the genus of Formula (7.2) and the genus of Formula (7.4), identified as Formula (7.2.1) and Formula (7.4.1), respectively, as well as the species of Formula (7.1.1) representing one of the above-mentioned additional isomers comprising a double replacement involving both first and second indazole isomers, and falling within the scope of the genus of Formula (7.1). 
Scheme 10 illustrates preparation of the bioisostere of Formula (7.1.1) above and begins with a starting material which is a species of Formula XV, whose preparation is illustrated in Scheme 2 above and is number L in Scheme 10. 
Scheme 11 set out below illustrates preparation of the bioisostere of Formula (7.2.1) above, wherein the starting material is readily available commercially or may be prepared by methods conventional in the art. 
Scheme 12 illustrates preparation of the bioisostere of Formula (7.4.1) above and begins with a starting material which is a species of Formula LXX and is readily available commercially or may be prepared by methods well known in the art, 
The above-described indazole bioisostere replacement compounds of the present invention may be utilized in the form of acids, esters, or other chemical classes of compounds to which the compounds described belong. It is also within the scope of the present invention to utilize those compounds in the form of pharmaceutically acceptable salts derived from various organic and inorganic acids and bases in accordance with procedures well known in the art. Such well-known pharmaceutically acceptable salts include, but are not limited to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, besylate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecysulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, isethionate, lactate, lactobionate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, salicylate, sodium phosphate, stearate, succinate, sulfate, sulfosalicylate, tartrate, thiocyanate, thiomalate, tosylate, and undecanoate.
Base salts of the indazole bioisostere replacement compounds of the present invention include, but are not limited to ammonium salts; alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; salts with organic bases such as dicyclohexylamine, meglumine, N-methyl-D-glucamine, tris-(hydroxymethyl)-methylamine (tromethamine), and salts with amino acids such as arginine, lysine, etc. Compounds of the present invention which comprise basic nitrogen-containing groups may be quatenized with such agents as (C1-C4) alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides, bromides and iodides; di(C1-C4) alkyl sulfate, e.g., dimethyl, diethyl and diamyl sulfates; (C10-C18) alkyl halides, e.g., decyl, dodecyl, lauryl, myristyl and and stearyl chlorides, bromides and iodides; and aryl-(C1-C4) alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such salts permit the preparation of both water-soluble and oil-soluble compounds of the present invention.
Among the above-recited pharmaceutical salts those which are preferred include, but are not limited to acetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate, and tromethamine.
Multiple salts forms are included within the scope of the present invention where a compound of the present invention contains more than one group capable of forming such pharmaceutically acceptable salts. Examples of typical multiple salt forms include, but are not limited to bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium, and trihydrochloride.
The pharmaceutical compositions of the present invention comprise any one or more of the above-described indazole bioisostere replacement compounds of the present invention, or a pharmaceutically acceptable salt thereof as also above-described, together with a pharmaceutically acceptable carrier in accordance with the properties and expected performance of such carriers which are well-known in the pertinent art.
The term xe2x80x9ccarrierxe2x80x9d as used herein includes acceptable diluents, excipient, adjuvants and vehicles. Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of this invention include but are not limited to, ion exchange compositions; alumina; aluminum stearate; lecithin; serum proteins, e.g., human serum albumin; phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes, e.g., prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica, magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; e.g., sodium carboxymethylcellulose; polyethylene glycol; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; and wool fat.
More particularly, the diluents, excipient, adjuvants and vehicles used in the pharmaceutical compositions of the present invention comprise members selected from the groups consisting essentially of the following: acidifying and allalizing agents added to obtain a desired or predetermined pH comprise acidifying agents, e.g., acetic acid, glacial acetic acid, malic acid, and propionic acid, and alkalizing agents, e.g., edetol, potassium carbonate, potassium hydroxide, sodium borate, sodium carbonate, and sodium hydroxide; aerosol propellants required where the pharmaceutical composition is to be delivered as an aerosol under significant pressure, e.g., acceptable halogenated hydrocarbons; nitrogen; or a volatile hydrocarbon such as butane, propane, isobutane or mixtures thereof; antimicrobial agents including antibacterial, antifungal and antiprotozoal agents added where the pharmaceutical composition is topically applied, e.g., antimicrobial agents such as benzyl alcohol, chlorobutanol, phenylethyl alcohol, phenylmercuric acetate, potassium sorbate, and sorbic acid, and antifungal agents such as benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, and sodium benzoate; antimicrobial preservatives added to the pharmaceutical compositions in order to protect them against the growth of potentially harmful microorganisms, e.g., alkyl esters of p-hydroxybenzoic acid, propionate salts, phenoxyethanol, methylparaben sodium, propylparaben sodium, sodium dehydroacetate, benzalkonium chloride, benzethonium chloride, and benzyl alcohol; antioxidants added to protect all of the ingredients of the pharmaceutical composition from damage or degradation by oxidizing agents present in the composition itself or the use environment, e.g., anoxomer, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, potassium metabisulfite, propyl octyl and dodecyl gallate, sodium metabisulfite, sulfur dioxide, and tocopherols; buffering agents used to maintain a desired pH of a composition once established, e.g., calcium acetate, potassium metaphosphate, potassium phosphate monobasic, and tartaric acid; and chelating agents used to help maintain the ionic strength of the pharmaceutical composition and bind to and effectively remove destructive compounds and metals, e.g., edetate dipotassium, edetate disodium, and edetic acid.
Dermatologically active agents are added to the pharmaceutical compositions of the present invention to be applied topically, e.g., wound healing agents such as peptide derivatives, yeast, panthenol, hexylresorcinol, phenol, tetracycline hydrochloride, lamin and kinetin, glucocorticosteroids for treating inflammation, e.g., hydrocortisone, dexamethasone, betamethasone, triamcinolone, fluocinolone and methylprednisolone, retinoids for treating acne, psoriasis, cutaneous aging, and skin cancer, e.g., retinol, tretinoin, isotretinoin, etretinate, acitretin, and arotinoid, immunosuppressive agents for treating inflammation, e.g., dapsone and sulfasalazine; mild antibacterial agents, e.g., resorcinol, salicylic acid, benzoyl peroxide, erythromycin-benzoyl peroxide, erythromycin, clindamycin, and mupirocin, antifungal agents, e.g., griseofulvin, azoles such as miconazole, econazole, itraconazole, fluconazole, and ketoconazole, and allylamines such as naftifine and terfinafine, antiviral agents, e.g., acyclovir, famciclovir, and valacyclovir, antihistamines, e.g., diphenhydramine, terfenadine, astemizole, loratadine, cetirizine, acrivastine, and temelastine, topical anesthetics, e.g., benzocaine, lidocaine, dibucaine, and pramoxine hydrochloride, topical analgesics, e.g., methyl salicylate, camphor, menthol, and resorcinol; topical antiseptics for preventing infection, e.g., benzalkonium chloride and povidone-iodine; vitamins and derivatives thereof such as tocopherol, tocopherol acetate, retinoic acid and retinol.
Further examples of diluents, excipient, adjuvants and vehicles used in the pharmaceutical compositions of the present invention comprise members selected from the groups consisting essentially of the following: dispersing and suspending agents, e.g., poligeenan, povidone, and silicon dioxide; emollients, e.g., hydrocarbon oils and waxes, triglyceride esters, acetylated monoglycerides, methyl and other alkyl esters of C10-C20 fatty acids, C10-C20 fatty acids, C10-C20 fatty alcohols, lanolin and derivatives, polyhydric alcohol esters such as polyethylene glycol (200-600), polyoxyethylene sorbitan fatty acid esters, wax esters, phospholipids, and sterols; emulsifying agents used for preparing oil-in-water emulsions; excipients, e.g., laurocapram and polyethylene glycol monomethyl ether; humectants, e.g., sorbitol, glycerin and hyaluronic acid; ointment bases, e.g., petrolatum, polyethylene glycol, lanolin, and poloxamer; penetration enhancers, e.g., dimethyl isosorbide, diethyl-glycol-monoethylether, 1-dodecylazacycloheptan-2-one, and dimethylsulfoxide (DMSO); preservatives, e.g., benzalkonium chloride, benzethonium chloride, alkyl esters of p-hydroxybenzoic acid, hydantoin derivatives, cetylpyridinium chloride, propylparaben, quaternary ammonium compounds such as potassium benzoate, and thimerosal; sequestering agents comprising cyclodextrins; solvents, e.g., acetone, alcohol, amylene hydrate, butyl alcohol, corn oil, cottonseed oil, ethyl acetate, glycerin, hexylene glycol, isopropyl alcohol, isostearyl alcohol, methyl alcohol, methylene chloride, mineral oil, peanut oil, phosphoric acid, polyethylene glycol, polyoxypropylene 15 stearyl ether, propylene glycol, propylene glycol diacetate, sesame oil, and purified water; stabilizers, e.g., calcium saccharate and thymol; surfactants, e.g., lapyrium chloride; laureth 4, i.e., xcex1-dodecyl-xcfx89-hydroxy-poly(oxy-1,2-ethanediyl) or polyethylene glycol monododecyl ether.
According to this invention, the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as do natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Rh, HCIX or similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation, as described above, or in a suitable enema formulation. Topically active transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspension in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation through the use of a nebulizer, a dry powder inhaler or a metered dose inhaler. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, hydrofluorocarbons, and/or other conventional solubilizing or dispersing agents.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration. It should be understood, however, that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredient may also depend upon the therapeutic or prophylactic agent, if any, with which the ingredient is co-administered.
The dosage and dose rate of the indazole bioisostere replacement compounds of this invention effective for preventing, inhibiting, suppressing or reducing the proximal and consequent or associated pathogenic processes subsequently mediated by the various endogenous ligands, receptors, enzymes, substrates, and regulatory and signal transduction entities herein described, will depend on a variety of factors, such as the nature of the ligand, etc., the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the observations and conclusions of the treating physician.
For example, where the dosage form is oral, e.g., a tablet or capsule, suitable dosage levels of the indazole bioisostere replacement compounds of the present invention will be between about 1.0 xcexcg and about 10.0 mg/kg body weight per day, preferably between about 5.0 xcexcg and about 5.0 mg/kg body weight per day, more preferably between about 10.0 xcexcg and about 1.0 mg/kg of body weight per day, and most preferably between about 20.0 xcexcg and about 0.5 mg/kg of body weight per day of the active ingredient.
Where the dosage form is topically administered to the bronchia and lungs, e.g., by means of a powder inhaler or nebulizer, suitable dosage levels of the indazole bioisostere replacement compounds of the present invention will be between about 0.1 xcexcg and about 1.0 mg/kg body weight per day, preferably between about 0.5 xcexcg and about 0.5 mg/kg body weight per day, more preferably between about 1.0 xcexcg and about 0.1 mg/kg of body weight per day, and most preferably between about 2.0 xcexcg and about 0.05 mg/kg of body weight per day of the active ingredient.
Using representative body weights of 10 kg and 100 kg in order to illustrate the range of daily topical dosages which might be used as described above, suitable dosage levels of the indazole bioisostere replacement compounds of the present invention will be between about 1.0-10.0 xcexcg and 10.0-100.0 mg per day, preferably between about 5.0-50.0 xcexcg and 5.0-50.0 mg per day, more preferably between about 10.0-100.0 xcexcg and 1.0-10.0 mg per day, and most perferably between about 20.0-200.0 xcexcg and about 0.5-5.0 mg per day of the active ingredient comprising an indazole bioisostere replacement compound of the present invention. These ranges of dosage amounts represent total dosage amounts of the active ingredient per day for a given patient. The number of times per day that a dose is administered will depend upon such pharmacological and pharmacokinetic factors as the half-life of the active ingredient, which reflects its rate of catabolism and clearance, as well as the minimal and optimal blood plasma or other body fluid levels of said active ingredient attained in the patient which are required for therapeutic efficacy
Numerous other factors must also be considered in deciding upon the number of doses per day and the amount of active ingredient per dose which will be administered. Not the least important of such other factors is the individual respsonse of the patient being treated. Thus, for example, where the active ingredient is used to treat or prevent asthma, and is administered topically via aerosol inhalation into the lungs, from one to four doses consisting of acuations of a dispensing device, i.e., xe2x80x9cpuffsxe2x80x9d of an inhaler, will be administered each day, each dose containing from about 50.0 xcexcg to about 10.0 mg of active ingredient.
For human use, the active indazole bioisostere replacement compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Such carriers have already been described in detail. In preferred embodiments, the indazole bioisostere replacement compounds of the present invention may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally; for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substance; for example, enough salts or glucose to make the solution isotonic. Additionally, the active compounds may be administered topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes, and ointments, in accordance with standard pharmaceutical practice.
The active indazole bioisostere replacement compounds of the present invention may also be administered to a mammal other than a human. The dosage to be administered to a mammal will depend on the animal species and the disease or disorder being treated. The active compounds may be administered to animals in the form of a capsule, bolus, tablet or liquid drench. The active compounds may also be administered to animals by injection or as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. As an alternative the indazole bioisostere replacement compounds of the present invention may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
Included within the scope of the present invention are embodiments comprising compositions which contain, in addition to an indazole bioisostere replacement compound of the present invention as active ingredient, additional therapeutic agent active ingredients selected from the group consisting essentially of anti-inflammatory corticosteroids; bronchodilators; antiaasthmatics; non-steroidal anti-inflammatories; immunosuppressants; immunostimulants; antimetabolites; antipsoriatics and antidiabetics. Specific compounds within each of these classes may be selected from those listed under the appropriate headings in Comprehensive Medicinal Chemistry, Pergamon Press, Oxford, England, pp. 970-986 (1990); and Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 9th ed., Hardman, J. G. and Limbird, L. E., eds., McGraw-Hill, 1996, the disclosure of which are incorporated herein by reference in their entireties. Especially preferred active ingredients to be included for use in combination with the compounds of Formula (I) are anti-inflammatory compounds such as theophylline, sulfasalazine and aminosalicylates; immunosuppressants such as cyclosporin, FK-506, and rapamycin; antimetabolites such as cyclophosphamide and methotrexate; and immunomodulators such as the interferons.
The following Examples further illustrate the invention, but they are not intended to be, nor should they be taken as in any way a limitation of the present invention. In the following examples, xe2x80x9cDMFxe2x80x9d means dimethylformamide, xe2x80x9cTHFxe2x80x9d means tetrahydrofuran, xe2x80x9cDMSOxe2x80x9d means dimethyl sulfoxide, and xe2x80x9cDMAPxe2x80x9d means 4-dimethylaminopyridine.